338 results on '"SMAC mimetics"'
Search Results
2. Multifaceted Evaluation of Inhibitors of Anti-Apoptotic Proteins in Head and Neck Cancer: Insights from In Vitro, In Vivo, and Clinical Studies (Review)
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Kamil Krzykawski, Robert Kubina, Dominika Wendlocha, Robert Sarna, and Aleksandra Mielczarek-Palacz
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apoptosis ,IAP ,HNSCC ,smac mimetics ,cancer ,head and neck ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
This paper presents a multifaceted assessment of inhibitors of anti-apoptotic proteins (IAPs) in the context of head and neck squamous cell carcinoma (HNSCC). The article discusses the results of in vitro, in vivo, and clinical studies, highlighting the significance of IAPs in the resistance of cancer cells to apoptosis, which is a key factor hindering effective treatment. The main apoptosis pathways, including the intrinsic and extrinsic pathways, and the role of IAPs in their regulation, are presented. The study’s findings suggest that targeting IAPs with novel therapies may offer clinical benefits in the treatment of advanced HNSCC, especially in cases resistant to conventional treatment methods. These conclusions underscore the need for further research to develop more effective and safer therapeutic strategies.
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- 2024
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3. Inhibition of Autophagy and the Cytoprotective Role of Smac Mimetic against ROS-Induced Cancer: A Potential Therapeutic Strategy in Relapse and Chemoresistance Cases in Breast Cancer
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Sahar Rafat, Mohammed Ageeli Hakami, Ali Hazazi, Ahad Amer Alsaiari, Summya Rashid, Mohammad Raghibul Hasan, Abdulaziz A. Aloliqi, Alaa Abdulaziz Eisa, Mohammad Irfan Dar, Mohd Faisal Khan, and Kapil Dev
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autophagy ,apoptosis ,ROS ,Smac mimetics ,cancer ,Biology (General) ,QH301-705.5 - Abstract
With more than a million deaths each year, breast cancer is the top cause of death in women. Around 70% of breast cancers are hormonally responsive. Although several therapeutic options exist, cancer resistance and recurrence render them inefficient and insufficient. The major key reason behind this is the failure in the regulation of the cell death mechanism. In addition, ROS was also found to play a major role in this problem. The therapeutic benefits of Smac mimetic compound (SMC) BV6 on MCF7 were examined in the current study. Treatment with BV6 reduces viability and induces apoptosis in MCF7 breast cancer cells. BV6 suppresses autophagy and has demonstrated a defensive role in cancer cells against oxidative stress caused by H2O2. Overall, the present investigation shows that SMC has therapeutic and cytoprotective potential against oxidative stress in cancer cells. These Smac mimetic compounds may be used as anti-cancer drugs as well as antioxidants alone or in conjunction with other commonly used antioxidants.
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- 2023
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4. Noncanonical-NF-κB activation and DDX3 inhibition reduces the HIV-1 reservoir by elimination of latently infected cells ex-vivo
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Jade Jansen, Stefanie Kroeze, Shirley Man, Matteo Andreini, Jan-Willem Bakker, Claudio Zamperini, Alessia Tarditi, Neeltje A. Kootstra, and Teunis B. H. Geijtenbeek
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HIV-1 reservoir ,human immunodeficiency virus ,DDX3 ,IAP ,latency reversal ,SMAC mimetics ,Microbiology ,QR1-502 - Abstract
ABSTRACT Latency reversal and subsequent elimination of the human immunodeficiency virus-1 (HIV-1) reservoir using a combination of compounds with different mechanisms of action are considered a promising tool for HIV-1 cure. Here, we analyzed HIV-1 reservoir reduction by targeting the two host factors; inhibitor of apoptosis proteins (IAPs) and DEAD-box polypeptide 3 (DDX3) using a SMAC mimetic (SMACm) and DDX3 inhibitor (DDX3i), respectively. We observed that SMACm efficiently reactivated HIV-1 in a latency Jurkat model, which was further enhanced by DDX3 inhibition. Strikingly, this compound combination strongly decreased the proportion of latently as well as transcriptionally active infected cells in a T cell line model with a dual-reporter virus. To determine the efficacy of compounds to eradicate the HIV-1 reservoir in people living with HIV (PWH), a novel ex vivo HIV-1 reservoir reduction assay (HIVRRA) was developed. DDX3i and SMACm alone reduced the HIV-1 reservoir in peripheral blood mononuclear cells (PBMCs) from the majority of PWH, whereas notably, the SMACm/DDX3i combination reduced the HIV-1 reservoir even further with 53%–90% in all PWH analyzed, while uninfected bystander cells were not affected. Our data highlight that IAPs as well as factors involved in HIV-1 replication like DDX3 are excellent targets for HIV-1 cure strategies. We show for the first time that the combination of SMACm and DDX3i reverses viral latency and specifically eliminates the HIV-1-infected cells in vitro and ex vivo. IMPORTANCE HIV-1 continues to be a major global health challenge. Current HIV-1 treatments are effective but need lifelong adherence. An HIV-1 cure should eliminate the latent viral reservoir that persists in people living with HIV-1. Different methods have been investigated that focus on reactivation and subsequent elimination of the HIV-1 reservoir, and it is becoming clear that a combination of compounds with different mechanisms of actions might be more effective. Here, we target two host factors, inhibitor of apoptosis proteins that control apoptosis and the DEAD-box helicase DDX3, facilitating HIV mRNA transport/translation. We show that targeting of these host factors with SMAC mimetics and DDX3 inhibitors induce reversal of viral latency and eliminate HIV-1-infected cells in vitro and ex vivo.
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- 2024
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5. Dual-targeting peptides@PMO, a mimetic to the pro-apoptotic protein Smac/DIABLO for selective activation of apoptosis in cancer cells.
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Di Giorgio, Eros, Ferino, Annalisa, Weizhe Huang, Simonetti, Sigrid, Luigi Xodo, and De Marco, Rossella
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APOPTOSIS ,PEPTIDES ,HELA cells ,CANCER cells ,INTEGRINS ,PROTEINS ,NANOPARTICLES - Abstract
The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3--integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure.
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Campbell, Grant R and Spector, Stephen A
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HIV-1 ,SMAC mimetics ,apoptosis ,autophagy ,autosis ,cell death ,latency promoting approach ,nanoparticle - Abstract
Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity-the "kick and kill" approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a "functional cure" where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission-a "block and lock" approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.
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- 2021
7. CD4+ T cell-mimicking nanoparticles encapsulating DIABLO/SMAC mimetics broadly neutralize HIV-1 and selectively kill HIV-1-infected cells
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Campbell, Grant R, Zhuang, Jia, Zhang, Gang, Landa, Igor, Kubiatowicz, Luke J, Dehaini, Diana, Fang, Ronnie H, Zhang, Liangfang, and Spector, Stephen A
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Prevention ,Biotechnology ,Immunization ,Infectious Diseases ,HIV/AIDS ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aetiology ,Infection ,Good Health and Well Being ,Adult ,Apoptosis ,Apoptosis Regulatory Proteins ,Autophagy ,Biomimetic Materials ,Biomimetics ,Broadly Neutralizing Antibodies ,CD4-Positive T-Lymphocytes ,Epitopes ,Female ,HIV Infections ,HIV-1 ,Healthy Volunteers ,Humans ,Male ,Mitochondrial Proteins ,Nanoparticle Drug Delivery System ,Nanoparticles ,Primary Cell Culture ,HIV ,nanoparticle ,SMAC mimetics ,autophagy ,neutralization ,Oncology and Carcinogenesis ,Oncology and carcinogenesis - Abstract
HIV-1 is a major global health challenge. The development of an effective vaccine and a therapeutic cure are top priorities. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 stymies this progress. Therapeutic strategies that provide effective and broad-spectrum neutralization against HIV-1 infection are highly desirable. Methods: We investigated the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) encapsulating the DIABLO/SMAC mimetics LCL-161 or AT-406 (also known as SM-406 or Debio 1143) to both neutralize HIV-1 and selectively kill HIV-1-infected resting CD4+ T cells and macrophages. Results: DIABLO/SMAC mimetic-loaded TNP displayed outstanding neutralizing breadth and potency, and selectively kill HIV-1-infected cells via autophagy-dependent apoptosis while having no drug-induced off-target or cytotoxic effects on bystander cells. Genetic inhibition of early stages of autophagy abolishes this effect. Conclusion: DIABLO/SMAC mimetic loaded TNP have the potential to be used as therapeutic agents to neutralize cell-free HIV-1 and to kill specifically HIV-1-infected cells as part of an HIV-1 cure strategy.
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- 2021
8. Dual-targeting peptides@PMO, a mimetic to the pro-apoptotic protein Smac/DIABLO for selective activation of apoptosis in cancer cells
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Eros Di Giorgio, Annalisa Ferino, Weizhe Huang, Sigrid Simonetti, Luigi Xodo, and Rossella De Marco
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Smac mimetics ,nanoparticles ,caspases ,oxaliplatin ,cervical cancer ,colorectal cancer ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3–integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types.
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- 2023
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9. Natural Flavonoids Quercetin and Kaempferol Targeting G2/M Cell Cycle-Related Genes and Synergize with Smac Mimetic LCL-161 to Induce Necroptosis in Cholangiocarcinoma Cells.
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Lomphithak, Thanpisit, Jaikla, Patthorn, Sae-Fung, Apiwit, Sonkaew, Sasiprapa, and Jitkaew, Siriporn
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Cholangiocarcinoma (CCA) is an aggressive cancer associated with a very poor prognosis and low survival rates, primarily due to late-stage diagnosis and low response rates to conventional chemotherapy. Therefore, there is an urgent need to identify effective therapeutic strategies that can improve patient outcomes. Flavonoids, such as quercetin and kaempferol, are naturally occurring compounds that have attracted significant attention for their potential in cancer therapy by targeting multiple genes. In this study, we employed network pharmacology and bioinformatic analysis to identify potential targets of quercetin and kaempferol. The results revealed that the target genes of these flavonoids were enriched in G2/M-related genes, and higher expression of G2/M signature genes was significantly associated with shorter survival in CCA patients. Furthermore, in vitro experiments using CCA cells demonstrated that quercetin or kaempferol induced cell-cycle arrest in the G2/M phase. Additionally, when combined with a Smac mimetic LCL-161, an IAP antagonist, quercetin or kaempferol synergistically induced RIPK1/RIPK3/MLKL-mediated necroptosis in CCA cells while sparing non-tumor cholangiocyte cells. These findings shed light on an innovative therapeutic combination of flavonoids, particularly quercetin and kaempferol, with Smac mimetics, suggesting great promise as a necroptosis-based approach for treating CCA and potentially other types of cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo
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Pache, Lars, Marsden, Matthew D, Teriete, Peter, Portillo, Alex J, Heimann, Dominik, Kim, Jocelyn T, Soliman, Mohamed SA, Dimapasoc, Melanie, Carmona, Camille, Celeridad, Maria, Spivak, Adam M, Planelles, Vicente, Cosford, Nicholas DP, Zack, Jerome A, and Chanda, Sumit K
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Human Fetal Tissue ,HIV/AIDS ,Biotechnology ,Infectious Diseases ,Infection ,Animals ,Anti-Retroviral Agents ,Bone Marrow ,Cells ,Cultured ,HIV Infections ,HIV Seropositivity ,HIV-1 ,Humans ,Liver ,Lymphocyte Activation ,Mice ,Mice ,Inbred C57BL ,NF-kappa B ,Signal Transduction ,Small Molecule Libraries ,T-Lymphocytes ,Thymus Gland ,Virus Activation ,Virus Latency ,Virus Replication ,BLT mouse model ,HIV ,HIV cure ,LRA ,Smac mimetics ,humanized mouse model ,latency ,latency reversal agents ,non-canonical NF-κB ,shock and kill ,Biomedical and clinical sciences - Abstract
"Shock and kill" strategies focus on purging the latent HIV-1 reservoir by treating infected individuals with therapeutics that activate the latent virus and subsequently eliminating infected cells. We have previously reported that induction of non-canonical nuclear factor κB (NF-κB) signaling through a class of small-molecule antagonists known as Smac mimetics can reverse HIV-1 latency. Here, we describe the development of Ciapavir (SBI-0953294), a molecule specifically optimized for HIV-1 latency reversal that was found to be more efficacious as a latency-reversing agent than other Smac mimetics under clinical development for cancer. Critically, this molecule induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.
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- 2020
11. SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.
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Shibuya, Yusuke, Kudo, Kei, Zeligs, Kristen P., Anderson, David, Hernandez, Lidia, Ning, Franklin, Cole, Christopher B., Fergusson, Maria, Kedei, Noemi, Lyons, John, Taylor, Jason, Korrapati, Soumya, and Annunziata, Christina M.
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IN vitro studies , *OVARIAN tumors , *INDOLE compounds , *IN vivo studies , *OLIGOPEPTIDES , *CELL physiology , *CANCER relapse , *APOPTOSIS , *SIGNAL peptides , *EARLY detection of cancer , *NF-kappa B , *CELLULAR signal transduction , *GENE expression , *DRUG synergism , *TUMOR necrosis factors , *RESEARCH funding , *HISTONE deacetylase , *CASPASES , *CHEMICAL inhibitors - Abstract
Simple Summary: The combination of a SMAC mimetic with an HDAC inhibitor is a novel and promising strategy for cancer treatment. The HDAC inhibitor mechanistically synergizes with SMAC mimetics by stimulating autocrine TNF-α production. The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Position of lipidation influences anticancer activity of Smac analogs
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Micewicz, Ewa D, Nguyen, Christine, Micewicz, Alina, Waring, Alan J, McBride, William H, and Ruchala, Piotr
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Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Chemical Sciences ,Rare Diseases ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Antineoplastic Agents ,Apoptosis Regulatory Proteins ,Cell Line ,Tumor ,Humans ,Mitochondrial Proteins ,Neoplasms ,Smac mimetics ,Anticancer agents ,Lipid-conjugated peptides ,S-alkylation of peptides ,Apoptosis ,Inhibitor of menin-MLL1 protein interactions ,Inhibitor of menin–MLL1 protein interactions ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s) in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipidated in positions 2, 3 and C-terminus was screened extensively in vitro against a total number of 50 diverse cancer cell lines revealing that both the position of lipidation as well as the type of lipid, influence their anti-cancer activity and cancer type specificity. Moreover, when used in combination therapy with inhibitor of menin-MLL1 protein interactions, position 2 modified analog SM2 showed strong synergistic anti-cancer properties. The most promising lipid-conjugated analogs SM2 and SM6, showed favorable pharmacokinetics and in vivo activity while administered subcutaneously in the preclinical mouse model. Collectively, our findings suggest that lipid modification of Smacs may be a viable approach in the development of anti-cancer therapeutic leads.
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- 2019
13. SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells
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Campbell, Grant R, Bruckman, Rachel S, Chu, Yen-Lin, Trout, Rodney N, and Spector, Stephen A
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Apoptosis ,Apoptosis Regulatory Proteins ,Autophagy ,Autophagy-Related Protein 5 ,Autophagy-Related Protein 7 ,Baculoviral IAP Repeat-Containing 3 Protein ,Beclin-1 ,Benzoquinones ,CD4-Positive T-Lymphocytes ,Caspase 8 ,Cell Death ,Cell Line ,Cyclohexanes ,Dipeptides ,Fas-Associated Death Domain Protein ,HIV Infections ,HIV-1 ,Humans ,Indoles ,Inhibitor of Apoptosis Proteins ,Intracellular Signaling Peptides and Proteins ,Mitochondrial Proteins ,Pyrroles ,Receptor-Interacting Protein Serine-Threonine Kinases ,Sequestosome-1 Protein ,Ubiquitin-Protein Ligases ,X-Linked Inhibitor of Apoptosis Protein ,BIRC2 ,CD4+ T cell ,Fas ,HIV ,RIPK1 ,SMAC mimetics ,XIAP ,apoptosis ,autophagy ,caspase 8 ,Microbiology ,Biochemistry and cell biology ,Medical microbiology - Abstract
Long-lived resting memory CD4+ T cells (TCM) are a major reservoir of latent HIV infection. We hypothesized that latent HIV-TCM cells are maintained by aberrant expression of cell survival factors, including XIAP, BIRC2/cIAP1, and beclin-1. DIABLO/SMAC mimetics are therapeutic agents that compromise cell survival by hijacking host apoptotic machinery. We found that DIABLO/SMAC mimetics (birinapant, GDC-0152, and embelin) selectively kill HIV-TCM without increasing virus production or targeting uninfected TCM. Treatment of HIV-TCM with DIABLO/SMAC mimetics promoted XIAP and BIRC2 degradation, which triggered autophagy and the formation of a cell death complex consisting of pro-apoptotic (FADD, RIPK1, RIPK3, and caspase 8) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacological inhibition of autophagy induction, but not autophagy-mediated degradation, abrogated this interaction and subsequent cell death. Our findings identify a mechanism whereby DIABLO/SMAC mimetics exploit autophagy and apoptotic machinery to selectively induce killing of HIV-TCM without viral reactivation while sparing uninfected cells.
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- 2018
14. LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling
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Arya Afsahi, Christopher M. Silvestri, Allyson E. Moore, Carly F. Graham, Kaylyn Bacchiochi, Martine St-Jean, Christopher L. Baker, Robert G. Korneluk, Shawn T. Beug, Eric C. LaCasse, and Jonathan L. Bramson
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SMAC mimetics ,engineered T cells ,LCL161 ,multiple myeloma ,cancer immunotherapy ,adoptive T cell therapies ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundThe genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics.MethodsWe have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology.ResultsLCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug’s effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161.ConclusionsOur results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis.
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- 2023
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15. X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.
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Carlet, Michela, Schmelz, Karin, Vergalli, Jenny, Herold, Tobias, Senft, Daniela, Jurinovic, Vindi, Hoffmann, Thomas, Proba, Jutta, Weichert, Nina, Junghanß, Christian, Roth, Mareike, Eschenburg, Georg, Barz, Malwine, Henze, Günter, Eckert, Cornelia, Eggert, Angelika, Zuber, Johannes, Hundsdoerfer, Patrick, and Jeremias, Irmela
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Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM‐sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy‐induced cell death via caspases and PARP, but independent from cIAP‐1/2, RIPK1, TNFα or NF‐κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA‐30 flanked shRNA expression in cell lines and patient‐derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown‐sensitized r/r ALL cells towards chemotherapy‐induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo, even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL. Synopsis: Smac mimetics sensitize relapsed/refractory acute leukemia (r/r ALL) cell lines towards chemotherapy, independently from TNFα, RIPK1, NFκB and cIAP1/2 signaling. Knockdown in PDX models shows that XIAP harbors an essential function in vivo and represents an important therapeutic target for r/r ALL. r/r ALL cell lines are sensitized to standard chemotherapy by co‐treatment with Smac mimetics (SM).TNFα, RIPK1, NFκB and cIAP1/2 are dispensable for apoptosis induced by the combination of SM and conventional chemotherapy in r/r ALL.To study the role of XIAP in vivo, a miR30‐based, fluorochrome‐guided system was established, with distinct promoters inducing different knockdown strengths.Moderate XIAP knockdown mimics the effects of SM and sensitizes r/r ALL to chemotherapy, making XIAP an interesting therapeutic target to enhance chemotherapy.In PDX models in vivo, strong XIAP knockdown alone reduces ALL growth, demonstrating that XIAP harbors an essential function and represents an interesting therapeutic target in r/r ALL. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma.
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Sunisa Prasopporn, Orawan Suppramote, Ben Ponvilawan, Chanette Jamyuang, Jantappapa Chanthercrob, Amphun Chaiboonchoe, Pimkanya More-Krong, Kamonchanok Kongsri, Monthira Suntiparpluacha, Rawisak Chanwat, Krittiya Korphaisarn, Seiji Okada, Somponnat Sampattavanich, and Siwanon Jirawatnotai
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MULTIDRUG resistance ,CISPLATIN ,CHOLANGIOCARCINOMA ,GEMCITABINE ,GASTROINTESTINAL cancer - Abstract
Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required. To that end - in this study, we developed several acquired GEM/CIS-resistant CCA cell lines and we screened those cell lines for acquired vulnerability. The screening process revealed that subset of CCA with GEM/CIS resistance acquired vulnerability to the small-molecule second mitochondrial-derived activator of caspases (SMAC) mimetics LCL161 and Birinapant. The observed acquired vulnerability was found to be associated with upregulation of an inhibitor of apoptosis protein 2 (cIAP2), a known target of SMAC mimetics. LCL161 or cIAP2-shRNA downregulated cIAP2 and restored the sensitivity to GEM/CIS in GEM/CIS-resistant CCA cell lines and in in vivo GEM/CIS-resistant xenograft models. A strong synergic effect was observed when LCL161 was added to GEM/CIS. Interestingly, this synergism was also observed in drug-naïve CCA cell lines, xenografts, and patient-derived organoids. This triplet therapy also prevented the emergence of multidrugresistant CCA in in vitro and in vivo models. Our findings suggest that activation of cIAP2 allows CCA to escape GEM/CIS, and that suppression of cIAP2 reestablishes the apoptotic profile of CCA, thus restoring its vulnerability to GEM/CIS. The results of this study indicate that combining the SMAC mimetic LCL161 with GEM/CIS inhibits and prevents the emergence of multidrug resistance in CCA. [ABSTRACT FROM AUTHOR]
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- 2022
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17. SMAC Mimetic BV6 Co-Treatment Downregulates the Factors Involved in Resistance and Relapse of Cancer: IAPs and Autophagy.
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Rafat, Sahar, Singh, Prabhakar, Pandey, Kamlesh Kumar, Almatroodi, Saleh A., Alsahli, Mohammed A., Almatroudi, Ahmad, Rahmani, Arshad Husain, and Dev, Kapil
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CANCER relapse , *TRAIL protein , *CELLULAR control mechanisms , *AUTOPHAGY , *CELL death , *CANCER cells , *BREAST - Abstract
Simple Summary: Breast cancer is the most prominent cancer among women. Therapeutic resistance and reoccurrence of cancer after various therapies, such as chemotherapy, radiotherapy etc., is the major cause of death. In various studies, it has been shown that dysregulation or defect in the cell death mechanisms such as apoptosis and autophagy is the key reason behind the issues. An increase in the level of inhibitors of apoptosis (IAPs) proteins and autophagy is founded in various cancers. Besides, the SMAC proteins that inhibit the action of IAPs are also found to be downregulated. In this study, BV6, a SMAC mimetic compound, not only induces apoptosis via inhibiting the action of IAPs but also downregulates autophagy. In addition, promising anticancer results were obtained after treating the breast cancer cells with BV6 in combination with death ligands such as TNF-related apoptosis-inducing ligand (TRAIL) and Tumor necrosis factor-α (TNF-α). It is an investigational study, and to the best of our knowledge, our study, for the first time, demonstrated the effect of BV6 on autophagy. This study presents the significance of SMAC mimetic compounds in the downregulation of factors responsible for cancer resistance and reoccurrence. The study may well provide a potent therapeutic target for the development of novel anti-cancer therapy using SMAC mimetics. Cancer is the utmost common disease-causing death worldwide, characterized by uncontrollable cell division with the potential of metastasis. Overexpression of the Inhibitors of Apoptosis proteins (IAPs) and autophagy correlates with tumorigenesis, therapeutic resistance, and reoccurrence after anticancer therapies. This study illuminates the role and efficacy of smac mimetic compound BV6 alone and in co-treatment with death ligands such as TRAIL and TNFα in the regulation of cell death mechanisms, i.e., apoptosis and autophagy. In this study, MTT assays, wound healing assays, and cellular and nuclear morphological studies were done. DAPI staining, AO/EtBr staining and AnnexinV/PI FACS was done to study the apoptosis. The expression of IAPs and autophagy biomarkers was analyzed using Real time-PCR and western blotting. Meanwhile, TEM demonstrated autophagy and cellular autophagic vacuoles in response to the BV6. The result shows a promising anti-cancer effect of BV6 alone as well as in combinational treatment with TRAIL and TNFα, compared to the lone treatment of TRAIL and TNFα in both breast cancer cell lines. The smac mimetic compound might provide an alternative combinational therapy with conventional anticancer therapies to tackle their inefficiency at the advanced stage of cancer, cancer resistance, and reoccurrence. Also, IAPs and autophagic proteins could act as potent target molecules for the development of novel anti-cancer drugs in pathogenesis and the betterment of regimens for cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
18. Current strategies to induce selective killing of HIV‐1‐infected cells.
- Author
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Campbell, Grant R. and Spector, Stephen A.
- Subjects
IMMUNOSUPPRESSION ,HIV ,ANTIRETROVIRAL agents - Abstract
Although combination antiretroviral therapy (ART) has led to significant HIV‐1 suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified ART. ART poses many challenges such as adherence to drug regimens, the emergence of resistant virus, and cumulative toxicity resulting from long‐term therapy. Moreover, latent HIV‐1 reservoir cells can be stochastically activated to produce viral particles despite effective ART and contribute to the rapid viral rebound that typically occurs within 2 weeks of ART interruption; thus, lifelong ART is required for continued viral suppression. Several strategies have been proposed to address the HIV‐1 reservoir such as reactivation of HIV‐1 transcription using latency reactivating agents with a combination of ART, host immune clearance and HIV‐1‐cytotoxicity to purge the infected cells—a "shock and kill" strategy. However, these approaches do not take into account the multiple transcriptional and translational blocks that contribute to HIV‐1 latency or the complex heterogeneity of the HIV‐1 reservoir, and clinical trials have thus far failed to produce the desired results. Here, we describe alternative strategies being pursued that are designed to kill selectively HIV‐1‐infected cells while sparing uninfected cells in the absence of enhanced humoral or adaptive immune responses. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
19. Modern Drug Discovery and Development in the Area of Cancer: Indian Context
- Author
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Kundu, Tapas K., Kulkarni, Anand P., Datta, Dipak, Sikder, Sweta, and Dikshit, Madhu, editor
- Published
- 2021
- Full Text
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20. Overview of the progress and prospects of SMAC mimetics in cancers: Is it a silver bullet?
- Author
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Almuradova Elvina, Malik Durr-E-Shahwar, Yousaf Sara, and Farooqi Ammad Ahmad
- Subjects
smac mimetics ,cancer treatment ,apoptosis ,metastasis ,tumor growth inhibition ,Pharmacy and materia medica ,RS1-441 - Abstract
Loss of apoptosis results in the survival and uncontrolled proliferation of cancer cells. Basic and clinical researchers have dissected myriads of central regulators of apoptosis. Second mitochondria-derived activator of caspases (SMAC)/ direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) has attracted phenomenal attention because of its amazing ability to trigger apoptotic death. Accordingly, different teams of interdisciplinary researchers are working on the design and development of SMAC mimetics which can significantly inhibit primary and secondary tumor growth.
- Published
- 2022
- Full Text
- View/download PDF
21. X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL
- Author
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Michela Carlet, Karin Schmelz, Jenny Vergalli, Tobias Herold, Daniela Senft, Vindi Jurinovic, Thomas Hoffmann, Jutta Proba, Nina Weichert, Christian Junghanß, Mareike Roth, Georg Eschenburg, Malwine Barz, Günter Henze, Cornelia Eckert, Angelika Eggert, Johannes Zuber, Patrick Hundsdoerfer, and Irmela Jeremias
- Subjects
PDX ,relapsed/refractory acute lymphoblastic leukemia ,smac mimetics ,therapeutic target ,XIAP ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM‐sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy‐induced cell death via caspases and PARP, but independent from cIAP‐1/2, RIPK1, TNFα or NF‐κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA‐30 flanked shRNA expression in cell lines and patient‐derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown‐sensitized r/r ALL cells towards chemotherapy‐induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo, even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL.
- Published
- 2023
- Full Text
- View/download PDF
22. Corrigendum: Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
- Author
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Sunisa Prasopporn, Orawan Suppramote, Ben Ponvilawan, Chanette Jamyuang, Jantappapa Chanthercrob, Amphun Chaiboonchoe, Pimkanya More-Krong, Kamonchanok Kongsri, Monthira Suntiparpluacha, Rawisak Chanwat, Krittiya Korphaisarn, Seiji Okada, Somponnat Sampattavanich, and Siwanon Jirawatnotai
- Subjects
SMAC mimetics ,LCL161 ,Gemcitabine plus Cisplatin therapy ,multidrug resistance ,cholangiocarcinoma ,acquired vulnerability ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
23. Natural Flavonoids Quercetin and Kaempferol Targeting G2/M Cell Cycle-Related Genes and Synergize with Smac Mimetic LCL-161 to Induce Necroptosis in Cholangiocarcinoma Cells
- Author
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Thanpisit Lomphithak, Patthorn Jaikla, Apiwit Sae-Fung, Sasiprapa Sonkaew, and Siriporn Jitkaew
- Subjects
Cholangiocarcinoma ,necroptosis ,Smac mimetics ,quercetin ,kaempferol ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Cholangiocarcinoma (CCA) is an aggressive cancer associated with a very poor prognosis and low survival rates, primarily due to late-stage diagnosis and low response rates to conventional chemotherapy. Therefore, there is an urgent need to identify effective therapeutic strategies that can improve patient outcomes. Flavonoids, such as quercetin and kaempferol, are naturally occurring compounds that have attracted significant attention for their potential in cancer therapy by targeting multiple genes. In this study, we employed network pharmacology and bioinformatic analysis to identify potential targets of quercetin and kaempferol. The results revealed that the target genes of these flavonoids were enriched in G2/M-related genes, and higher expression of G2/M signature genes was significantly associated with shorter survival in CCA patients. Furthermore, in vitro experiments using CCA cells demonstrated that quercetin or kaempferol induced cell-cycle arrest in the G2/M phase. Additionally, when combined with a Smac mimetic LCL-161, an IAP antagonist, quercetin or kaempferol synergistically induced RIPK1/RIPK3/MLKL-mediated necroptosis in CCA cells while sparing non-tumor cholangiocyte cells. These findings shed light on an innovative therapeutic combination of flavonoids, particularly quercetin and kaempferol, with Smac mimetics, suggesting great promise as a necroptosis-based approach for treating CCA and potentially other types of cancer.
- Published
- 2023
- Full Text
- View/download PDF
24. Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines
- Author
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Annkathrin Koch, Birte Jeiler, Jens Roedig, Sjoerd J.L. van Wijk, Nadezda Dolgikh, and Simone Fulda
- Subjects
Smac mimetics ,TRAIL ,Burkitt's lymphoma ,Necroptosis ,MLKL ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Burkitt's lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin's lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL.
- Published
- 2021
- Full Text
- View/download PDF
25. Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics
- Author
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Cai, Jing, Lin, Yuan, Zhang, Haipeng, Liang, Jiankai, Tan, Yaqian, Cavenee, Webster K, and Yan, Guangmei
- Subjects
Gene Therapy ,Cancer ,Genetics ,Aetiology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Animals ,Apoptosis ,Bystander Effect ,Cell Line ,Tumor ,Cytokines ,Humans ,Mice ,Neoplasms ,Experimental ,Oligopeptides ,Oncolytic Viruses ,Peptidomimetics ,Virus Replication ,oncolytic virus ,SMAC mimetics ,bystander killing effect - Abstract
Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.
- Published
- 2017
26. A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer.
- Author
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Cetraro, Pierina, Plaza-Diaz, Julio, MacKenzie, Alex, and Abadía-Molina, Francisco
- Subjects
- *
ENDOPLASMIC reticulum , *SIGNAL peptides , *APOPTOSIS , *GENE expression , *DNA-binding proteins , *IMMUNITY , *TUMOR necrosis factors , *TUMORS , *CASPASES , *DRUG resistance in cancer cells , *CHEMICAL inhibitors - Abstract
Simple Summary: The Inhibitor of Apoptosis (IAP) family of proteins has emerged as a potential pharmacological target in cancer. Abnormal expression of IAPs can lead to dysregulated cell suicide, promoting the development of different pathologies. In several cancer types, members of this protein family are overexpressed while their natural antagonist (Smac) appears to be downregulated, contributing to the acquisition of resistance to traditional therapy. The development of compounds that mimic the action of Smac showed promise in the re-sensitization of the cell suicide defense mechanism in cancer cells, particularly in combination with other treatments. Interaction with other molecules, such as tumor necrosis factor-α, in the tumor microenvironment reveals a complex interplay between IAPs and cancer. The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), have been implicated in mediating its effects. As a result, abnormal expression of inhibitor apoptosis proteins (IAPs) can lead to dysregulated apoptosis promoting the development of different pathologies. In several cancer types IAPs are overexpressed, while their natural antagonist, the second mitochondrial-derived activator of caspases (Smac), appears to be downregulated, potentially contributing to the acquisition of resistance to traditional therapy. Recently developed Smac mimetics counteract IAP activity and show promise in the re-sensitization to apoptosis in cancer cells. Given the modest impact of Smac mimetics when used as a monotherapy, pairing of these compounds with other treatment modalities is increasingly being explored. Modulation of molecules such as tumor necrosis factor-α (TNF-α) present in the tumor microenvironment have been suggested to contribute to putative therapeutic efficacy of IAP inhibition, although published results do not show this consistently underlining the complex interaction between IAPs and cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
27. Cell adhesion tunes inflammatory TPL2 kinase signal transduction.
- Author
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Vougioukalaki, Maria, Georgila, Konstantina, Athanasiadis, Emmanouil I., and Eliopoulos, Aristides G.
- Abstract
Signaling through adhesion-related molecules is important for cancer growth and metastasis and cancer cells are resistant to anoikis, a form of cell death ensued by cell detachment from the extracellular matrix. Herein, we report that detached carcinoma cells and immortalized fibroblasts display defects in TNF and CD40 ligand (CD40L)-induced MEK-ERK signaling. Cell detachment results in reduced basal levels of the MEK kinase TPL2, compromises TPL2 activation and sensitizes carcinoma cells to death-inducing receptor ligands, mimicking the synthetic lethal interactions between TPL2 inactivation and TNF or CD40L stimulation. Focal Adhesion Kinase (FAK), which is activated in focal adhesions and mediates anchorage-dependent survival signaling, was found to sustain steady state TPL2 protein levels and to be required for TNF-induced TPL2 signal transduction. We show that when FAK levels are reduced, as seen in certain types of malignancy or malignant cell populations, the formation of cIAP2:RIPK1 complexes increases, leading to reduced TPL2 expression levels by a dual mechanism: first, by the reduction in the levels of NF-κΒ1 which is required for TPL2 stability; second, by the engagement of an RelA NF-κΒ pathway that elevates interleukin-6 production, leading to activation of STAT3 and its transcriptional target SKP2 which functions as a TPL2 E3 ubiquitin ligase. These data underscore a new mode of regulation of TNF family signal transduction on the TPL2-MEK-ERK branch by adhesion-related molecules that may have important ramifications for cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
28. Toward conditional control of Smac mimetic activity by RNA‐templated reduction of azidopeptides on PNA or 2′‐OMe‐RNA.
- Author
-
Altrichter, Yannic, Schöller, Justus, and Seitz, Oliver
- Abstract
Oligonucleotide templated reactions can be used to control the activity of functional molecules based on the presence of a specific trigger sequence. We report an RNA‐controlled reaction system to conditionally restore the N‐terminal amino group and thus binding affinity of azide‐modified Smac mimetic compounds (SMCs) for their target protein X‐linked Inhibitor of Apoptosis Protein (XIAP). Two templated reactions were compared: Staudinger reduction with phosphines and a photocatalytic reaction with Ru(bpy)2(mcbpy). The latter proved faster and more efficient, especially for the activation of a bivalent SMC, which requires two consecutive reduction steps. The templated reaction proceeds with turnover when 2′‐OMe‐RNA probes are used, but is significantly more efficient with PNA, catalyzing a reaction in the presence of low, substoichiometric amounts (1%‐3%, 10 nM) of target RNA. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
29. SMAC Mimetics as Therapeutic Agents in HIV Infection.
- Author
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Molyer, Bengisu, Kumar, Ashok, and Angel, Jonathan B.
- Subjects
HIV infections ,CELL survival ,PROTEIN expression ,ANTIRETROVIRAL agents ,CASPASES - Abstract
Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4
+ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
30. RIPK1‐mediated immunogenic cell death promotes anti‐tumour immunity against soft‐tissue sarcoma
- Author
-
Henry G Smith, Kunzah Jamal, Jasbani HS Dayal, Tencho Tenev, Joan Kyula‐Currie, Naomi Guppy, Patrycja Gazinska, Victoria Roulstone, Gianmaria Liccardi, Emma Davies, Ioannis Roxanis, Alan A Melcher, Andrew J Hayes, Gareth J Inman, Kevin J Harrington, and Pascal Meier
- Subjects
apoptosis ,RIPK1 ,SMAC mimetics ,soft‐tissue sarcoma ,TNF ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti‐tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term “immunogenic cell death” is not fully defined, activation of receptor‐interacting serine/threonine‐protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre‐clinical application of an in vivo treatment protocol for soft‐tissue sarcoma that directly engages RIPK1‐mediated immunogenic cell death. We find that RIPK1‐mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1‐induced cell death in patients with advanced disease at limb extremities.
- Published
- 2020
- Full Text
- View/download PDF
31. SMAC Mimetics as Therapeutic Agents in HIV Infection
- Author
-
Bengisu Molyer, Ashok Kumar, and Jonathan B. Angel
- Subjects
SMAC mimetics ,HIV ,HIV latency ,apoptosis ,HIV therapeutics ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4+ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy.
- Published
- 2021
- Full Text
- View/download PDF
32. Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication.
- Author
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Yin X, Pu Y, Yuan S, Pache L, Churas C, Weston S, Riva L, Simons LM, Cisneros WJ, Clausen T, De Jesus PD, Kim HN, Fuentes D, Whitelock J, Esko J, Lord M, Mena I, García-Sastre A, Hultquist JF, Frieman MB, Ideker T, Pratt D, Martin-Sancho L, and Chanda SK
- Abstract
Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased towards the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published datasets to reveal pathways supported by orthogonal datasets, including transcriptional regulation, epigenetic modifications, and MAPK signalling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 27 proteins that were determined to impact assembly and release. Additionally, a subset of proteins were tested across other coronaviruses revealing 17 potential pan-coronavirus targets. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry, and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo . These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals., Competing Interests: COMPETING INTERESTS STATEMENT J.F.H. has received research support, paid to Northwestern University, from Gilead Sciences, and is a paid consultant for Merck. The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer and Prosetta, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, Astrazeneca and Novavax. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. All other authors declare no competing interests.
- Published
- 2024
- Full Text
- View/download PDF
33. SMAC Mimetic BV6 Co-Treatment Downregulates the Factors Involved in Resistance and Relapse of Cancer: IAPs and Autophagy
- Author
-
Sahar Rafat, Prabhakar Singh, Kamlesh Kumar Pandey, Saleh A. Almatroodi, Mohammed A. Alsahli, Ahmad Almatroudi, Arshad Husain Rahmani, and Kapil Dev
- Subjects
autophagy ,apoptosis ,IAPs ,smac mimetics ,breast cancer ,TRAIL ,Biology (General) ,QH301-705.5 - Abstract
Cancer is the utmost common disease-causing death worldwide, characterized by uncontrollable cell division with the potential of metastasis. Overexpression of the Inhibitors of Apoptosis proteins (IAPs) and autophagy correlates with tumorigenesis, therapeutic resistance, and reoccurrence after anticancer therapies. This study illuminates the role and efficacy of smac mimetic compound BV6 alone and in co-treatment with death ligands such as TRAIL and TNFα in the regulation of cell death mechanisms, i.e., apoptosis and autophagy. In this study, MTT assays, wound healing assays, and cellular and nuclear morphological studies were done. DAPI staining, AO/EtBr staining and AnnexinV/PI FACS was done to study the apoptosis. The expression of IAPs and autophagy biomarkers was analyzed using Real time-PCR and western blotting. Meanwhile, TEM demonstrated autophagy and cellular autophagic vacuoles in response to the BV6. The result shows a promising anti-cancer effect of BV6 alone as well as in combinational treatment with TRAIL and TNFα, compared to the lone treatment of TRAIL and TNFα in both breast cancer cell lines. The smac mimetic compound might provide an alternative combinational therapy with conventional anticancer therapies to tackle their inefficiency at the advanced stage of cancer, cancer resistance, and reoccurrence. Also, IAPs and autophagic proteins could act as potent target molecules for the development of novel anti-cancer drugs in pathogenesis and the betterment of regimens for cancer.
- Published
- 2022
- Full Text
- View/download PDF
34. Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines.
- Author
-
Koch, Annkathrin, Jeiler, Birte, Roedig, Jens, van Wijk, Sjoerd J.L., Dolgikh, Nadezda, and Fulda, Simone
- Subjects
- *
BURKITT'S lymphoma , *CELL lines , *LYMPHOMAS - Abstract
Burkitt's lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin's lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
35. X-Linked IAP
- Author
-
Noonan, Anne and Marshall, John L., editor
- Published
- 2017
- Full Text
- View/download PDF
36. IAPs and Resistance to Death Receptors in Cancer
- Author
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Dubrez, Laurence, Fulda, Simone, Bonavida, Benjamin, Series editor, and Micheau, Olivier, editor
- Published
- 2017
- Full Text
- View/download PDF
37. Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo
- Author
-
Lars Pache, Matthew D. Marsden, Peter Teriete, Alex J. Portillo, Dominik Heimann, Jocelyn T. Kim, Mohamed S.A. Soliman, Melanie Dimapasoc, Camille Carmona, Maria Celeridad, Adam M. Spivak, Vicente Planelles, Nicholas D.P. Cosford, Jerome A. Zack, and Sumit K. Chanda
- Subjects
HIV ,latency ,Smac mimetics ,latency reversal agents ,LRA ,non-canonical NF-κB ,Medicine (General) ,R5-920 - Abstract
Summary: “Shock and kill” strategies focus on purging the latent HIV-1 reservoir by treating infected individuals with therapeutics that activate the latent virus and subsequently eliminating infected cells. We have previously reported that induction of non-canonical nuclear factor κB (NF-κB) signaling through a class of small-molecule antagonists known as Smac mimetics can reverse HIV-1 latency. Here, we describe the development of Ciapavir (SBI-0953294), a molecule specifically optimized for HIV-1 latency reversal that was found to be more efficacious as a latency-reversing agent than other Smac mimetics under clinical development for cancer. Critically, this molecule induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.
- Published
- 2020
- Full Text
- View/download PDF
38. Proteasome inhibitors and Smac mimetics cooperate to induce cell death in diffuse large B‐cell lymphoma by stabilizing NOXA and triggering mitochondrial apoptosis.
- Author
-
Dietz, Anna, Dalda, Nahide, Zielke, Svenja, Dittmann, Jessica, Wijk, Sjoerd J.L., Vogler, Meike, and Fulda, Simone
- Subjects
CELL death ,PROTEASOME inhibitors ,APOPTOSIS ,DIFFUSE large B-cell lymphomas ,CASPASE inhibitors ,LYMPHOMAS ,BORTEZOMIB ,ANAPLASTIC lymphoma kinase - Abstract
Copy number gains and increased expression levels of cellular Inhibitor of Apoptosis protein (cIAP)1 and cIAP2 have been identified in primary diffuse large B‐cell lymphoma (DLBCL) tissues. Second mitochondria‐derived activator of caspases (Smac) mimetics were designed to antagonize IAP proteins. However, since their effect as single agents is limited, combination treatment represents a strategy for their clinical development. Therefore, we investigated the Smac mimetic BV6 in combination with proteasome inhibitors and analyzed the molecular mechanisms of action. We discovered that BV6 treatment sensitizes DLBCL cells to proteasome inhibition. We show a synergistic decrease in cell viability and induction of apoptosis by BV6/Carfilzomib (CFZ) treatment, which was confirmed by calculation of combination index (CI) and Bliss score. BV6 and CFZ acted together to trigger activation of BAX and BAK, which facilitated cell death, as knockdown of BAX and BAK significantly reduced BV6/CFZ‐mediated cell death. Activation of BAX and BAK was accompanied by loss of mitochondrial membrane potential (MMP) and activation of caspases. Pretreatment with the caspase inhibitor N‐benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethylketone (zVAD.fmk) rescued BV6/CFZ‐induced cell death, confirming caspase dependency. Treatment with CFZ alone or in combination with BV6 caused accumulation of NOXA, which was required for cell death, as gene silencing by siRNA or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9‐mediated NOXA inactivation inhibited BV6/CFZ‐induced cell death. Together, these experiments indicate that BV6 and CFZ cooperatively induce apoptotic cell death via the mitochondrial pathway. These findings emphasize the role of Smac mimetics for sensitizing DLBCL cells to proteasome inhibition with important implications for further (pre)clinical studies. What's new? Diffuse large B‐cell lymphoma (DLBCL) is a heterogenous disease, in which existing immunochemotherapy fails in about 40 percent of patients. In particular, poor outcome in DLBCL is correlated with elevated expression of X‐chromosome‐linked inhibitor of apoptosis (XIAP) protein. Here, the Smac mimetic BV6, designed to antagonize XIAP, was found to sensitize DLBCL cells to proteasome inhibition. Combination treatment using BV6 and proteasome inhibitors synergistically induced cell death, which relied on BAX/BAK activation and NOXA accumulation. The findings suggest that combined use of Smac mimetics and proteasome inhibitors is a promising strategy to improve the clinical management of DLBCL. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
39. Sensitization of head and neck squamous cell carcinoma to apoptosis by combinational SMAC mimetic and Fas ligand-Fc treatment in vitro.
- Author
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Brands, Roman C., Scheurer, Mario J.J., Hartmann, Stefan, Seher, Axel, Freudlsperger, Christian, Moratin, Julius, Linz, Christian, Kübler, Alexander C., and Müller-Richter, Urs D.A.
- Subjects
SQUAMOUS cell carcinoma ,CELL lines ,APOPTOSIS ,INTRA-abdominal pressure ,ANTINEOPLASTIC agents ,BCL genes - Abstract
This study aimed to investigate the in vitro efficacy of three different SMAC mimetics for pro-apoptotic sensitization of HNSCC cells. We evaluated BV-6 in comparison to Birinapant and LCL161, for which pro-apoptotic sensitization effects have been demonstrated. Concentration-dependent response was measured for BV-6 in each cell line with an average IC 50 value 8-fold lower than of aforementioned SMAC mimetics. Combination treatment of FasL (log2) and BV-6 (IC 10) showed highly significant cell count reductions even in the lowest applied concentration in five cell lines (PCI-1: p = 0.0002, PCI-13: p = 0.0002, Detroit 562: p: p < 0.0001, FaDu: p < 0.0001, SCC-25: p = 0.0047). Synergistic effects (y < 1) were evident in eight out of 10 cell lines (PCI-1, PCI-9, PCI-13, PCI-68, Detroit 562, FaDu, SCC-25 and HaCaT). Annexin V assays revealed in nine cell lines very highly significant (p < 0.001) pro-apoptotic effects of BV-6. Western blots showed a heterogeneous IAP expression following SMAC mimetic treatment. Except for two cell lines, at least the cellular inhibitor of apoptosis protein 1 (cIAP1) was degraded in response to BV-6. For prospective targeted HNSCC therapy, this study identifies SMAC mimetics, particularly BV-6 as the compound with the highest pro-apoptotic potency, as promising antitumor agents. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
40. RIPK1‐mediated immunogenic cell death promotes anti‐tumour immunity against soft‐tissue sarcoma.
- Author
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Smith, Henry G, Jamal, Kunzah, Dayal, Jasbani HS, Tenev, Tencho, Kyula‐Currie, Joan, Guppy, Naomi, Gazinska, Patrycja, Roulstone, Victoria, Liccardi, Gianmaria, Davies, Emma, Roxanis, Ioannis, Melcher, Alan A, Hayes, Andrew J, Inman, Gareth J, Harrington, Kevin J, and Meier, Pascal
- Abstract
Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti‐tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term "immunogenic cell death" is not fully defined, activation of receptor‐interacting serine/threonine‐protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre‐clinical application of an in vivo treatment protocol for soft‐tissue sarcoma that directly engages RIPK1‐mediated immunogenic cell death. We find that RIPK1‐mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1‐induced cell death in patients with advanced disease at limb extremities. Synopsis: The pathways that initiate and execute immunogenic cell death are complex, genetically encoded, and subject to significant regulation. This study focusses on the possibility to engage RIPK1‐mediated immunogenic cell death for the treatment of soft tissue sarcomas that occur at limb extremities. Inhibition of IAPs via small‐molecule SMAC mimetics potently sensitised extremity malignancies to the standard‐of‐care treatment TNF/Melphalan.Co‐treatment with SMAC mimetics converted non‐immunogenic intrinsic apoptosis to Ripk1‐assisted immunogenic cell death.Ripk1‐induced cell death augmented tumour immune infiltration, delayed tumour growth and prolonged survival.Combination therapy with SMAC mimetics and checkpoint inhibitors further prolonged recurrence‐free survival following isolated limb perfusion‐mediated TNF/Mel treatment.SMAC mimetics improved anti‐tumour immunity of standard‐of‐care treatment for soft tissue sarcomas that occur at limb extremities. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
41. Inhibition of Autophagy and the Cytoprotective Role of Smac Mimetic against ROS-Induced Cancer: A Potential Therapeutic Strategy in Relapse and Chemoresistance Cases in Breast Cancer
- Author
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Dev, Sahar Rafat, Mohammed Ageeli Hakami, Ali Hazazi, Ahad Amer Alsaiari, Summya Rashid, Mohammad Raghibul Hasan, Abdulaziz A. Aloliqi, Alaa Abdulaziz Eisa, Mohammad Irfan Dar, Mohd Faisal Khan, and Kapil
- Subjects
autophagy ,apoptosis ,ROS ,Smac mimetics ,cancer - Abstract
With more than a million deaths each year, breast cancer is the top cause of death in women. Around 70% of breast cancers are hormonally responsive. Although several therapeutic options exist, cancer resistance and recurrence render them inefficient and insufficient. The major key reason behind this is the failure in the regulation of the cell death mechanism. In addition, ROS was also found to play a major role in this problem. The therapeutic benefits of Smac mimetic compound (SMC) BV6 on MCF7 were examined in the current study. Treatment with BV6 reduces viability and induces apoptosis in MCF7 breast cancer cells. BV6 suppresses autophagy and has demonstrated a defensive role in cancer cells against oxidative stress caused by H2O2. Overall, the present investigation shows that SMC has therapeutic and cytoprotective potential against oxidative stress in cancer cells. These Smac mimetic compounds may be used as anti-cancer drugs as well as antioxidants alone or in conjunction with other commonly used antioxidants.
- Published
- 2023
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- View/download PDF
42. Natural Flavonoids Quercetin and Kaempferol Targeting G2/M Cell Cycle-Related Genes and Synergize with Smac Mimetic LCL-161 to Induce Necroptosis in Cholangiocarcinoma Cells
- Author
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Jitkaew, Thanpisit Lomphithak, Patthorn Jaikla, Apiwit Sae-Fung, Sasiprapa Sonkaew, and Siriporn
- Subjects
Cholangiocarcinoma ,necroptosis ,Smac mimetics ,quercetin ,kaempferol - Abstract
Cholangiocarcinoma (CCA) is an aggressive cancer associated with a very poor prognosis and low survival rates, primarily due to late-stage diagnosis and low response rates to conventional chemotherapy. Therefore, there is an urgent need to identify effective therapeutic strategies that can improve patient outcomes. Flavonoids, such as quercetin and kaempferol, are naturally occurring compounds that have attracted significant attention for their potential in cancer therapy by targeting multiple genes. In this study, we employed network pharmacology and bioinformatic analysis to identify potential targets of quercetin and kaempferol. The results revealed that the target genes of these flavonoids were enriched in G2/M-related genes, and higher expression of G2/M signature genes was significantly associated with shorter survival in CCA patients. Furthermore, in vitro experiments using CCA cells demonstrated that quercetin or kaempferol induced cell-cycle arrest in the G2/M phase. Additionally, when combined with a Smac mimetic LCL-161, an IAP antagonist, quercetin or kaempferol synergistically induced RIPK1/RIPK3/MLKL-mediated necroptosis in CCA cells while sparing non-tumor cholangiocyte cells. These findings shed light on an innovative therapeutic combination of flavonoids, particularly quercetin and kaempferol, with Smac mimetics, suggesting great promise as a necroptosis-based approach for treating CCA and potentially other types of cancer.
- Published
- 2023
- Full Text
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43. IAP Family of Proteins as Therapeutic Targets for Acute Myeloid Leukemia
- Author
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Carter, Bing Z., Andreeff, Michael, El-Deiry, Wafik, Series editor, and Andreeff, Michael, editor
- Published
- 2015
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- View/download PDF
44. Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure
- Author
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Grant R. Campbell and Stephen A. Spector
- Subjects
HIV-1 ,autophagy ,latency promoting approach ,cell death ,nanoparticle ,SMAC mimetics ,Cytology ,QH573-671 - Abstract
Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.
- Published
- 2021
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45. Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium
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Uris Ros, Aida Peña-Blanco, Kay Hänggi, Ulrich Kunzendorf, Stefan Krautwald, W. Wei-Lynn Wong, and Ana J. García-Sáez
- Subjects
necroptosis ,calcium signaling ,Smac mimetics ,membrane pores ,TNF ,Biology (General) ,QH301-705.5 - Abstract
Necroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux. We also demonstrate that necroptotic plasma membrane rupture is mediated by osmotic forces and membrane pores around 4 nm in diameter. This late permeabilization step represents a hallmark in necroptosis execution that is cell and treatment independent and requires the RIP1/RIP3/MLKL core. In support of this, treatment with osmoprotectants reduces cell damage in an in vivo necroptosis model of ischemia-reperfusion injury.
- Published
- 2017
- Full Text
- View/download PDF
46. Noncanonical-NF-κB activation and DDX3 inhibition reduces the HIV-1 reservoir by elimination of latently infected cells ex-vivo .
- Author
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Jansen J, Kroeze S, Man S, Andreini M, Bakker J-W, Zamperini C, Tarditi A, Kootstra NA, and Geijtenbeek TBH
- Subjects
- Humans, NF-kappa B metabolism, CD4-Positive T-Lymphocytes, Gene Expression Regulation, Virus Latency, HIV-1, HIV Infections drug therapy, HIV Infections genetics
- Abstract
Importance: HIV-1 continues to be a major global health challenge. Current HIV-1 treatments are effective but need lifelong adherence. An HIV-1 cure should eliminate the latent viral reservoir that persists in people living with HIV-1. Different methods have been investigated that focus on reactivation and subsequent elimination of the HIV-1 reservoir, and it is becoming clear that a combination of compounds with different mechanisms of actions might be more effective. Here, we target two host factors, inhibitor of apoptosis proteins that control apoptosis and the DEAD-box helicase DDX3, facilitating HIV mRNA transport/translation. We show that targeting of these host factors with SMAC mimetics and DDX3 inhibitors induce reversal of viral latency and eliminate HIV-1-infected cells in vitro and ex vivo ., Competing Interests: M.A., J.B., C.Z., and A.T. are employees of First Health Pharmaceuticals B.V.
- Published
- 2024
- Full Text
- View/download PDF
47. SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects.
- Author
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Pandey R, Bisht P, Wal P, Murti K, Ravichandiran V, and Kumar N
- Subjects
- Humans, Intracellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Apoptosis drug effects, Animals, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Apoptosis Regulatory Proteins metabolism, Mitochondrial Proteins metabolism, Mitochondrial Proteins antagonists & inhibitors
- Abstract
Background: Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades., Objective: This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer., Method: Articles were analysed using search engines and databases namely Pubmed and Scopus., Result: Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation., Conclusion: SMAC mimetics acts in a restorative way in the prevention of lung cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2024
- Full Text
- View/download PDF
48. Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.
- Author
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Kikuchi S, Sugama Y, Takada K, Kamihara Y, Wada A, Arihara Y, Nakamura H, and Sato T
- Subjects
- Humans, Interleukin-6, Cell Line, Tumor, Apoptosis, Inhibitor of Apoptosis Proteins metabolism, Inhibitor of Apoptosis Proteins pharmacology, X-Linked Inhibitor of Apoptosis Protein metabolism, X-Linked Inhibitor of Apoptosis Protein pharmacology, Multiple Myeloma drug therapy
- Abstract
Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C
58 H78 N8 O8 ), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest to disclose., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
49. Programmed Necrosis/Necroptosis: An Inflammatory Form of Cell Death
- Author
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Chan, Francis Ka-Ming and Wu, Hao, editor
- Published
- 2014
- Full Text
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50. Targeting inhibitors of apoptosis in oral squamous cell carcinoma in vitro.
- Author
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Scheurer, Mario J.J., Seher, Axel, Steinacker, Valentin, Linz, Christian, Hartmann, Stefan, Kübler, Alexander C., Müller-Richter, Urs D.A., and Brands, Roman C.
- Subjects
SQUAMOUS cell carcinoma ,APOPTOSIS ,CELL death ,HEAD & neck cancer ,CANCER cells ,CETUXIMAB - Abstract
Head and neck cancer, which predominantly arises from the oral mucosa, represents the sixth most common malignancy worldwide. These cancer cells can be resistant to programmed cell death triggered by extrinsic stimuli due to innate overexpression of inhibitor of apoptosis proteins (IAPs). The cellular protein second mitochondria-derived activator of caspases (SMAC) can antagonize IAP-induced caspase inhibition and thus trigger apoptosis. Here, we investigate the cell death-sensitizing effects of the SMAC mimetic LCL161 alone and in combination with Fas ligand (FasL) using a panel of six cell lines. Fas receptor (FasR) expression was analyzed by flow cytometry. Cells were treated with FasL and LCL161 alone or in combination, and cytotoxicity was measured using crystal violet assays. Annexin V and cell viability assays using zVAD-fmk and Necrostatin-1 (Nec-1) were carried out to assess the type of programmed cell death induced by LCL161. To demonstrate the sensitizing effects of LCL161, we employed the t-test to compare the effects of FasL alone and in combination with LCL161. Linear regression analysis was performed to determine initial and half maximal inhibitory concentrations (IC 10 and IC 50 , respectively). Distinct FasR expression was detected in each cell line. Four of six cell lines were significantly sensitized to FasL by LCL161 (p < 0.05), and synergistic effects were observed (y < 1). Moreover, the initially resistant cell line SCC-25 was effectively sensitized to FasL by LCL161. Annexin V FACS analysis demonstrated apoptosis-sensitizing and apoptosis-inducing effects of LCL161 across all cell lines. Using specific cell death inhibitors (zVAD-fmk and Nec-1), we demonstrated that LCL161-initiated apoptosis could not be prevented, highlighting the proapoptotic potential of this mimetic in these cells. Our findings show the effectiveness of apoptotic sensitization of OSCC cells by LCL161 in combination with FasL, thus confirming the importance of an IAP-targeting therapeutic approach for oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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