Search

Background: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. Results: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. Conclusion: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19. [ABSTRACT FROM AUTHOR]

The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes. [ABSTRACT FROM AUTHOR]

Immunotherapy is one of the most promising anti-cancer treatment. It involves activating the host's own immune system to eliminate cancer cells. Activation of cGAS-STING pathway is promising therapeutic approach for cancer immunotherapy. However, in human clinical trials, targeting cGAS-STING pathway results in insufficient or unsustainable anti-tumor response. To enhance its effectiveness, combination with other anti-cancer therapies seems essential to achieve synergistic systemic anti-tumor response. The aim of this study was to evaluate whether the combination of STING agonist-cGAMP with anti-vascular RGD-(KLAKLAK)2 peptide results in a better anti-tumor response in poorly immunogenic tumors with various STING protein and αvβ3 integrin status. Combination therapy inhibited growth of murine breast carcinoma more effectively than melanoma. In melanoma, the administration of STING agonist alone was sufficient to obtain a satisfactory therapeutic effect. In both tumor models we have noted stimulation of innate immune response following cGAMP administration alone or in combination. The largest population of immune cells infiltrating the TME after therapy were activated NK cells. Increased infiltration of cytotoxic CD8+ T lymphocytes within the TME was only observed in melanoma tumors. However, they also expressed the "exhaustion" PD-1 receptor. In contrast, in breast carcinoma tumors each therapy caused the drop in the number of infiltrating CD8+ T cells. The obtained results indicate an additional therapeutic benefit from combining STING agonist with an anti-vascular agent. However, this effect depends on the type of tumor, the status of its microenvironment and the expression of specific proteins such as STING and αvβ3 family integrin. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) ranks as the most prevalent of primary liver cancers and stands as the third leading cause of cancer-related deaths. Early-stage HCC can be effectively managed with available treatment modalities ranging from invasive techniques, such as liver resection and thermoablation, to systemic therapies primarily employing tyrosine kinase inhibitors. Unfortunately, these interventions take a significant toll on the body, either through physical trauma or the adverse effects of pharmacotherapy. Consequently, there is an understandable drive to develop novel HCC therapies. Adipose-derived stem cells (ADSCs) are a promising therapeutic tool. Their facile extraction process, coupled with the distinctive immunomodulatory capabilities of their secretome, make them an intriguing subject for investigation in both oncology and regenerative medicine. The factors they produce are both enzymes affecting the extracellular matrix (specifically, metalloproteinases and their inhibitors) as well as cytokines and growth factors affecting cell proliferation and invasiveness. So far, the interactions observed with various cancer cell types have not led to clear conclusions. The evidence shows both inhibitory and stimulatory effects on tumor growth. Notably, these effects appear to be dependent on the tumor type, prompting speculation regarding their potential inhibitory impact on HCC. This review briefly synthesizes findings from preclinical and clinical studies examining the effects of ADSCs on cancers, with a specific focus on HCC, and emphasizes the need for further research. [ABSTRACT FROM AUTHOR]

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is a highly invasive malignancy and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) as its most prevalent histological subtype. Despite all breakthroughs achieved in drug development, the prognosis of NSCLC remains poor. The mitogen-activated protein kinase signaling cascade (MAPKC) is a complex network of interacting molecules that can drive oncogenesis, cancer progression, and drug resistance when dysregulated. Over the past decades, MAPKC components have been used to design MAPKC inhibitors (MAPKCIs), which have shown varying efficacy in treating NSCLC. Thus, recent studies support the potential clinical use of MAPKCIs, especially in combination with other therapeutic approaches. This article provides an overview of the MAPKC and its inhibitors in the clinical management of NSCLC. It addresses the gaps in the current literature on different combinations of selective inhibitors while suggesting two particular therapy approaches to be researched in NSCLC: parallel and aggregate targeting of the MAPKC. This work also provides suggestions that could serve as a potential guideline to aid future research in MAPKCIs to optimize clinical outcomes in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is a primary bone malignancy that mostly affects young people, characterized by high metastatic potential, and a marked chemoresistance that is responsible for disease relapse in most patients. Therefore, it is necessary to identify novel molecules to setup targeted strategies to improve the clinical outcome. The enzyme nicotinamide N‐methyltransferase (NNMT) catalyses the N‐methylation of nicotinamide and other analogs, playing a crucial role in the biotransformation of drugs and xenobiotics. NNMT overexpression was reported in a wide variety of cancers, and several studies demonstrated that is able to promote cell proliferation, migration and resistance to chemotherapy. The aim of this study was to explore the potential involvement of NNMT in OS. Methods: Immunohistochemical analyses have been performed to evaluate NNMT expression in selected OS and healthy bone tissue samples. Subsequently, OS cell lines have been transfected with vectors targeting NNMT mRNA (shRNAs) and the impact of this downregulation on migration, cell proliferation, and response to chemotherapeutic treatment was also analysed by wound healing, MTT, SRB and Trypan blue assays, respectively. Results: Results showed that OS samples display a significantly higher NNMT expression compared with healthy tissue. Preliminary results suggest that NNMT silencing in OS cell lines is associated to a decrease of cell proliferation and migration, as well as to enhanced sensitivity to chemotherapy. Data obtained showed that NNMT may represent an interesting marker for OS detection and a promising target for effective anti‐cancer therapy. [ABSTRACT FROM AUTHOR]

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumorspecific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient's clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-g following oncovirotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to oncovirotherapy at the early stage of the preclinical phases. [ABSTRACT FROM AUTHOR]

Simple Summary: Nasopharyngeal carcinoma (NPC) is an epithelial cancer associated with Epstein–Barr virus (EBV) infection. EBV infection contributes to not only the tumorigenesis of NPC but also the formation of a complicated tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells are lymphoid members of the innate immune system exhibiting both anti-tumor and anti-virus abilities. The cytokine and cellular interaction features of NK cells are distinct from those of CD8+ cytotoxic T cells. This unique characteristic has not been fully described in EBV+ NPC. This review provides an overview of the complicated crosstalk between NK cells and the TIME of EBV+ NPC and potential therapeutic strategies. A new perspective is proposed to direct future exploration. Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein–Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations. [ABSTRACT FROM AUTHOR]

Fang Yang,1,* Cong Li,2,* Yuling Qiu,1 Xinjie Chen,3 Kelin Zheng,4 Donglin Kang,5 Yin Zhang,2 Baorui Liu,1 Yongzhong Yao,2 Li Xie1 1The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China; 2Department of Breast Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 3The Comprehensive Cancer Center, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, People’s Republic of China; 4Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 5Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Xie, The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China, Email xieli@njglyy.com Yongzhong Yao, Department of Breast Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China, Tel/Fax +86-025-83106666, Email yyz1006@hotmail.comPurpose: The coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has delayed medical consultations, especially for patients receiving intravenous anti-cancer therapy. We aim to investigate alterations in immune function among breast cancer patients who experience delayed intravenous therapy due to SARS-CoV-2 infection.Patients and Methods: We performed an observational investigation of breast cancer patients in Nanjing Drum Tower Hospital from December 27, 2022, to January 20, 2023. Patients who recovered from SARS-CoV-2 infection were eligible for enrollment. Peripheral blood samples were taken prior to the restart of intravenous anti-cancer therapy to examine hematologic parameters.Results: A total of 131 patients were included in the final analysis. Cough (74.0%), fever (62.6%), and expectoration (46.6%) were identified as the most presenting symptoms of SARS-CoV-2 infection in breast cancer. The average nucleic acid conversion time and delayed treatment time was 13.4 days and 13.9 days, respectively. The patients > 60 years old experienced prolonged nucleic acid conversion time (P = 0.017) and delayed treatment time (P = 0.028) compared to those

Nano-sized biomaterials are innovative drug carriers with nanometric dimensions. Designed with biocompatibility in mind, they enable precise drug delivery while minimizing side effects. Controlled release of therapeutic substances enhances efficacy, opening new possibilities for treating neurological and oncological diseases. Integrated diagnostic-therapeutic nanosystems allow real-time monitoring of treatment effectiveness, which is crucial for therapy personalization. Utilizing biomaterials as nano-sized carriers in conjunction with drugs represents a promising direction that could revolutionize the field of pharmaceutical therapy. Such carriers represent groundbreaking drug delivery systems on a nanometric scale, designed with biocompatibility in mind, enabling precise drug delivery while minimizing side effects. Using biomaterials in synergy with drugs demonstrates significant potential for a revolutionary impact on pharmaceutical therapy. Conclusions drawn from the review indicate that nano-sized biomaterials constitute an innovative tool that can significantly improve therapy effectiveness and safety, especially in treating neurological and oncological diseases. These findings should guide researchers towards further studies to refine nano-sized biomaterials, assess their effectiveness under various pathological conditions, and explore diagnostic-therapeutic applications. Ultimately, these results underscore the promising nature of nano-sized biomaterials as advanced drug carriers, ushering in a new era in nanomedical therapy. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is a primary treatment for cancer, but its efficacy is often limited by cancer-associated bacteria (CAB) that impair tumor suppressor functions. Our previous research found that Mycoplasma fermentans DnaK, a chaperone protein, impairs p53 activities, which are essential for most anti-cancer chemotherapeutic responses. Methods: To investigate the role of DnaK in chemotherapy, we treated cancer cell lines with M. fermentans DnaK and then with commonly used p53-dependent anti-cancer drugs (cisplatin and 5FU). We evaluated the cells' survival in the presence or absence of a DnaK-binding peptide (ARV-1502). We also validated our findings using primary tumor cells from a novel DnaK knock-in mouse model. To provide a broader context for the clinical significance of these findings, we investigated human primary cancer sequencing datasets from The Cancer Genome Atlas (TCGA). We identified F. nucleatum as a CAB carrying DnaK with an amino acid composition highly similar to M. fermentans DnaK. Therefore, we investigated the effect of F. nucleatum DnaK on the anti-cancer activity of cisplatin and 5FU. Results: Our results show that both M. fermentans and F. nucleatum DnaKs reduce the effectiveness of cisplatin and 5FU. However, the use of ARV-1502 effectively restored the drugs' anti-cancer efficacy. Conclusions: Our findings offer a practical framework for designing and implementing novel personalized anti-cancer strategies by targeting specific bacterial DnaKs in patients with poor response to chemotherapy, underscoring the potential for microbiome-based personalized cancer therapies. [ABSTRACT FROM AUTHOR]

A versatile method for the automated synthesis of composites containing DNA‐oligonucleotides and boron cluster scaffolds and their assembly into functional nanoparticles is described. The obtained, torus‐like nanoparticles carry antisense oligonucleotides that target two different oncogenes simultaneously. The nanoparticles exhibited notable silencing efficiency in vitro in a pancreatic carcinoma cell line PANC‐1 toward EGFR and c‐Myc genes at the mRNA level, and a significant efficiency at the protein level. The proposed approach may be an attractive alternative to methods currently used, including one therapeutic nucleic acid, one genetic target, or the use of cocktails of therapeutic nucleic acids. [ABSTRACT FROM AUTHOR]

At most of the times, patients who are diagnosed with kidney cancer should be provided with systemic treatment as drug resistance is a challenging issue in the treatment of this disease. The progression of the cancer can be inhibited with the help of mTOR inhibitors namely RAD001 (everolimus) and MTI-31. In literature, it has been revealed that these mTOR inhibitors have the potential to stimulate autophagy. This degradation pathway boosts the survival rate of the cancerous cells that are subjected to anti-cancer therapy. In this study, CCK8, colony formation assays, and ethynyl deoxyuridine (EdU) analysis were conducted to detect cell proliferation. Furthermore, Transwell assays were also conducted for cell migration analysis. In addition to these, the researchers also performed the flow cytometry process to identify the cells that are undergoing apoptosis. In vivo, experiments were conducted to measure the growth of tumors and metastasis. In this study, the treatment provided through a combination of MTI-31 and RAD001 significantly inhibited the kidney cancer cells' proliferation and tumor growth. Furthermore, there was a notable reduction in the migration and invasion of kidney cancer cells upon the neighboring cells. The outcomes from the mechanistic studies infer that the combination of MTI-31 and RAD001 increases the LC3 levels, which in turn translates into the activation of autophagy. To conclude, the combination of MTI-31 and RAD001 improves the anti-cancerous impact produced by RAD001 in vivo through the promotion of autophagy. [ABSTRACT FROM AUTHOR]

Anti-cancer therapy based on oncolytic viruses (OVs) is a targeted approach that takes advantage of OVs' ability to selectively infect and replicate in tumor cells, activate the host immune response, and destroy malignant cells over healthy ones. Vesicular stomatitis virus (VSV) is known for its wide range of advantages: a lack of pre-existing immunity, a genome that is easily amenable to manipulation, and rapid growth to high titers in a broad range of cell lines, to name a few. VSV-induced tumor immunity can be enhanced by the delivery of immunostimulatory cytokines. The targeted cytokine delivery to tumors avoids the significant toxicity associated with systemic delivery while also boosting the immune response. To demonstrate this enhanced effect on both tumor growth and survival, a novel recombinant VSV (rVSV)-mIL12-mGMCSF, co-expressing mouse IL-12 (interleukin-12) and GM-CSF (granulocyte-macrophage colony-stimulating factor), was tested alongside rVSV-dM51-GFP (rVSV-GFP) that was injected intratumorally in a syngeneic in vivo C57BL/6 mouse model infused subcutaneously with B16-F10 melanoma cells. The pilot study tested the effect of two viral injections 4 days apart and demonstrated that treatment with the two rVSVs resulted in partial inhibition of tumor growth (TGII of around 40%) and an increased survival rate in animals from the treatment groups. The effect of the two VSVs on immune cell populations will be investigated in future in vivo studies with an optimized experimental design with multiple higher viral doses, as a lack of this information presents a limitation of this study. [ABSTRACT FROM AUTHOR]

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumor-specific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient’s clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-γ following onco-virotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to onco-virotherapy at the early stage of the preclinical phases.

The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.

Lung cancer (LC) is a highly invasive malignancy and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) as its most prevalent histological subtype. Despite all breakthroughs achieved in drug development, the prognosis of NSCLC remains poor. The mitogen-activated protein kinase signaling cascade (MAPKC) is a complex network of interacting molecules that can drive oncogenesis, cancer progression, and drug resistance when dysregulated. Over the past decades, MAPKC components have been used to design MAPKC inhibitors (MAPKCIs), which have shown varying efficacy in treating NSCLC. Thus, recent studies support the potential clinical use of MAPKCIs, especially in combination with other therapeutic approaches. This article provides an overview of the MAPKC and its inhibitors in the clinical management of NSCLC. It addresses the gaps in the current literature on different combinations of selective inhibitors while suggesting two particular therapy approaches to be researched in NSCLC: parallel and aggregate targeting of the MAPKC. This work also provides suggestions that could serve as a potential guideline to aid future research in MAPKCIs to optimize clinical outcomes in NSCLC.

Hepatocellular carcinoma (HCC) ranks as the most prevalent of primary liver cancers and stands as the third leading cause of cancer-related deaths. Early-stage HCC can be effectively managed with available treatment modalities ranging from invasive techniques, such as liver resection and thermoablation, to systemic therapies primarily employing tyrosine kinase inhibitors. Unfortunately, these interventions take a significant toll on the body, either through physical trauma or the adverse effects of pharmacotherapy. Consequently, there is an understandable drive to develop novel HCC therapies. Adipose-derived stem cells (ADSCs) are a promising therapeutic tool. Their facile extraction process, coupled with the distinctive immunomodulatory capabilities of their secretome, make them an intriguing subject for investigation in both oncology and regenerative medicine. The factors they produce are both enzymes affecting the extracellular matrix (specifically, metalloproteinases and their inhibitors) as well as cytokines and growth factors affecting cell proliferation and invasiveness. So far, the interactions observed with various cancer cell types have not led to clear conclusions. The evidence shows both inhibitory and stimulatory effects on tumor growth. Notably, these effects appear to be dependent on the tumor type, prompting speculation regarding their potential inhibitory impact on HCC. This review briefly synthesizes findings from preclinical and clinical studies examining the effects of ADSCs on cancers, with a specific focus on HCC, and emphasizes the need for further research.

Copper is an essential metal ion that is involved in critical cellular processes, but which can also exhibit toxic effects through its ability to catalyze reactive oxygen species (ROS) formation. Dysregulation of copper homeostasis has been implicated in the progression of several diseases, including cancer. A novel therapeutic approach, extensively studied in recent years, is to capitalize on the increased copper uptake and dependency exhibited by cancer cells and to promote copper-associated ROS production within the tumor microenvironment, leading to the apoptosis of cancer cells. Such an effect can be achieved by selectively chelating copper from copper-bearing metalloproteins in cancer cells, thereby forming a copper–chelator complex that produces ROS and, through this, induces oxidative stress and initiates apoptosis. Herein, we describe a peptoid chelator, TB, that is highly suitable to carry this task. Peptoids are N-substituted glycine oligomers that can be efficiently synthesized on a solid support and are also biocompatible; thus, they are considered promising drug candidates. We show, by rigorous spectroscopic techniques, that TB is not only selective for Cu(II) ions, but can also effectively extract copper from metallothionein-2, and the formed complex CuTB can promote ROS production. Our findings present a promising first example for the future development of peptoid-based chelators for applications in anti-cancer chelation therapy, highlighting the potential for the prospect of peptoid chelators as therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent improvements in survival rates, colorectal cancer is still responsible for millions of premature deaths worldwide. A better understanding of the steps that lead from chronic inflammation to cancer progression could offer new therapeutic options and save many lives. The present study aimed to investigate the role of the transcription factor signal transducer and activator of transcription 2 (STAT2) in colorectal cancer by taking advantage of experimental mouse models and three-dimensional tumoroids. Our results indicate that STAT2 promotes colorectal cancer by various mechanisms and that anti-cancer drugs could easily kill tumor cells lacking STAT2. It is conceivable that future therapeutic strategies for colorectal cancer might try to mitigate the actions of STAT2 to improve the treatment outcome in affected patients. Colorectal cancer (CRC) is a significant socioeconomic burden in modern society and is accountable for millions of premature deaths each year. The role of signal transducer and activator of transcription 2 (STAT2)-dependent signaling in this context is not yet fully understood, and no therapies targeting this pathway are currently being pursued. We investigated the role of STAT2 in CRC using experimental mouse models coupled with RNA-sequencing (RNA-Seq) data and functional assays with anti-cancer agents in three-dimensional tumoroids. Stat2−/− mice showed greater resistance to the development of CRC in both inflammation-driven and inflammation-independent experimental CRC models. In ex vivo studies, tumoroids derived from Stat2−/− mice with the multiple intestinal neoplasia (Min) mutant allele of the adenomatous polyposis coli (Apc) locus exhibited delayed growth, were overall smaller and more differentiated as compared with tumoroids from ApcMin/+ wildtype (WT) mice. Notably, tumoroids from ApcMin/+ Stat2−/− mice were more susceptible to anti-cancer agents inducing cell death by different mechanisms. Our findings clearly indicated that STAT2 promotes CRC and suggested that interventions targeting STAT2-dependent signals might become an attractive therapeutic option for patients with CRC. [ABSTRACT FROM AUTHOR]

Enzymatische Reaktionen können endogene Nährstoffe eines Tumors verbrauchen und zytotoxische Spezies erzeugen und sind daher vielversprechende Werkzeuge für die Behandlung bösartiger Tumore. Inspiriert von der Natur, in der Enzyme in Membranen kompartimentiert sind, um eine hohe Reaktionseffizienz zu erreichen und biologische Prozesse von der Umwelt zu trennen, entwickelten wir liposomale Nanoreaktoren, die enzymatische Kaskadenreaktionen im wässrigen Nanoconfinement des Liposoms durchführen können. Die Nanoreaktoren hemmten das Tumorwachstum in vivo effektiv, indem sie Tumornährstoffe (Glukose und Sauerstoff) verbrauchten und hochgradig zytotoxische Hydroxylradikale (⋅OH) produzierten. Die Ko‐Kompartimentierung von Glukoseoxidase (GOx) und Meerrettichperoxidase (HRP) in Liposomen konnte die lokale Konzentration des Zwischenprodukts Wasserstoffperoxid (H2O2) sowie den Säuregrad aufgrund der Bildung von Gluconsäure durch GOx erhöhen. Sowohl H2O2 als auch der Säuregehalt beschleunigten die zweite Stufe der Reaktion durch HRP und verbesserten so die Gesamteffizienz der Kaskadenreaktion. Die biomimetische Kompartimentierung enzymatischer Tandemreaktionen in biokompatiblen Liposomen ist ein vielversprechender Weg für die Entwicklung katalytischer Nanomedikamente für die Antitumortherapie. [ABSTRACT FROM AUTHOR]

Anti-cancer therapy has been a significant focus of research. Developing and marketing various types and mechanisms of anti-cancer therapies benefit a variety of patients significantly. The long-term benefit to patients in evaluating the risk-benefit ratio of anti-cancer therapy has become a significant concern. This paper discusses the evaluation of long-term efficacy within the estimand framework and summarizes the various strategies for addressing potential intercurrent events. Non-proportional hazards of survival data may arise with novel anti-cancer therapies, leading to potential bias in conventional evaluation methods. This paper reviews statistical methods for addressing this issue, including novel endpoints, hypothesis testing, and efficacy estimation methods. We also discuss the influences of treatment switching. Although advanced methods have been developed to address the non-proportional hazard, they still have limitations that require continued collaborative efforts to resolve issues. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a highgrade neoplasm of skeletal myoblast-like cells. About 40% of all registered soft tissue tumors are RMSs. This paper describes our current understanding of the RMS subtypes (alveolar (ARMS), embryonic (ERMS), pleomorphic (PRMS), and spindle cell/sclerosing (s/scRMS)), diagnostic methods, molecular bases, and characteristics. We also present the currently used treatment methods and the potential use of natural substances in the treatment of this type of cancer. Natural cytotoxic substances are compounds that have been the subject of numerous studies and discussions in recent years. Since anti-cancer therapies are often limited by a low therapeutic index and cancer resistance to pharmacotherapy, it is very important to search for new, effective compounds. Additionally, compounds of a natural origin are usually readily available and have a reduced cytotoxicity. Thus, the undiscovered potential of natural anti-cancer compounds makes this field of research a very important area. The introduction of model species into research examining the use of natural cytostatic therapies for RMS will allow for further assessment of the effects of these compounds on cancerous and healthy tissues. [ABSTRACT FROM AUTHOR]

For their full manifestation, tumors require support from the surrounding tumor microenvironment (TME), which includes a specific extracellular matrix (ECM), vasculature, and a variety of non-malignant host cells. Together, these components form a tumor-permissive niche that significantly differs from physiological conditions. While the TME helps to promote tumor progression, its special composition also provides potential targets for anti-cancer therapy. Targeting tumor-specific ECM molecules and stromal cells or disrupting aberrant mesenchyme-cancer communications might normalize the TME and improve cancer treatment outcome. The tenascins are a family of large, multifunctional extracellular glycoproteins consisting of four members. Although each have been described to be expressed in the ECM surrounding cancer cells, tenascin-C and tenascin-W are currently the most promising candidates for exploitability and clinical use as they are highly expressed in various tumor stroma with relatively low abundance in healthy tissues. Here, we review what is known about expression of all four tenascin family members in tumors, followed by a more thorough discussion on tenascin-C and tenascin-W focusing on their oncogenic functions and their potential as diagnostic and/or targetable molecules for anti-cancer treatment purposes.

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.

Heat shock proteins (HSPs) represent cellular chaperones that are classified into several families, including HSP27, HSP40, HSP60, HSP70, and HSP90. The role of HSPs in the cell includes the facilitation of protein folding and maintaining protein structure. Both processes play crucial roles during stress conditions in the cell such as heat shock, degradation, and hypoxia. Moreover, HSPs are important modulators of cellular proliferation and differentiation, and are strongly associated with the molecular orchestration of carcinogenesis. The expression and/or activity of HSPs in cancer cells is generally abnormally high and is associated with increased metastatic potential and activity of cancer stem cells, more pronounced angiogenesis, downregulated apoptosis, and the resistance to anticancer therapy in many patients. Based on the mentioned reasons, HSPs have strong potential as valid diagnostic, prognostic, and therapeutic biomarkers in clinical oncology. In addition, numerous papers describe the role of HSPs as chaperones in the regulation of immune responses inside and outside the cell. Importantly, highly expressed/activated HSPs may be inhibited via immunotherapeutic targets in various types of cancers. The aim of this work is to provide a comprehensive overview of the relationship between HSPs and the tumor cell with the intention of highlighting the potential use of HSPs in personalized cancer management. [ABSTRACT FROM AUTHOR]

Breast cancer is considered the most commonly diagnosed tumors. Biomarkers used for the diagnosis and treatment of breast cancer are: tissue biomarkers (PR, ER, HER2, Ki-67) and serum biomarkers (CA-15-3, CA-125, CA-27-29, CEA, cytokeratins). ECD HER2, metalloproteinases and leptin are emerging as promising biomarkers for breast cancer. There is a growing need for personalized diagnostics based on tumour genome characterization, relying on a liquid biopsy containing components such as CTC and ctDNA, cell-free RNA. Biomarkers can also be used use as a target for anti-breast cancer treatment (PGRN and sortilin, AR, PD-1/PD-L1). Another potential field of application of breast cancer biomarkers is monitoring treatment side effects, such us inflammatory biomarkers causing cardiotoxicity, thyroiditis biomarkers (TSH, FT4, TPOab TgAb) in IrAE, NF-L and MCP-1 in ICI-associated neurotoxity. It is expected that new prognostic and predictive biomarkers will be developed that can provide accurate and reliable information for clinical application. Through the recognition of emerging biomarkers, it is possible to identify subgroups of patients who benefit from targeted therapies and managing treatment by monitoring side effects. However, these new biomarkers need to be validated and tested for their suitability before entering clinical use. [ABSTRACT FROM AUTHOR]

Female infertility is a significant health issue worldwide with a rising incidence. Anti-cancer therapy is one of the most important reasons for increasing infertility. Although anti-cancer treatment increases the rate of survival, it decreases the quality of life through its side effects. The most substantial side effects are sexual dysfunction and infertility. Breast cancer is the most common cancer. The first-line treatment of breast cancer is chemotherapy by alkylating agents like cyclophosphamide, which leads to infertility. For instance, persistent chemotherapy-induced amenorrhea among breast cancer patients could affect almost half of the patients that undergo such therapy. However, some agents or therapeutic methods can ameliorate these intoxicating effects. Chemotherapy plus gonadotropin-releasing hormone agonist, in breast cancer patients, can not only improve overall survival but also reduce ovarian toxicity. Age plays an essential role in chemotherapy-induced amenorrhea. Chemotherapy at a younger age can reduce the risk of infertility. Gynecological cancers including uterine and ovarian cancer, which have high mortality rates, are the most related cancers to infertility. Surgery is the primary treatment of gynecological cancers. Studies demonstrated that fertility-sparing surgery is a better option than radical surgery. In addition, neoadjuvant chemotherapy is mostly a better option than primary cytoreductive surgery in terms of survival and fertility. Immune checkpoint inhibitors (ICIs) have recently played a major role in treating various cancer types. However, ICIs are associated with hypophysitis, which affects ovaries and can lead to infertility. There are some options for ovarian preservation such as embryo cryopreservation, oocyte cryopreservation, ovarian transposition, ovarian tissue cryopreservation, and ovarian suppression by GnRH agonists. Anti-müllerian hormone level can be utilized to monitor the ovarian reserve. Moreover, to avoid fertility loss, approaches such as using transplantation of human placenta mesenchymal stem cells, administrating anti-inflammatory agents and hormone therapy are under investigation. [ABSTRACT FROM AUTHOR]

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein–Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

Melanoma is a highly malignant skin cancer that is known for its resistance to treatments. In recent years, there has been significant progress in the study of non-apoptotic cell death, such as pyroptosis, ferroptosis, necroptosis, and cuproptosis. This review provides an overview of the mechanisms and signaling pathways involved in non-apoptotic cell death in melanoma. This article explores the interplay between various forms of cell death, including pyroptosis, necroptosis, ferroptosis, and cuproptosis, as well as apoptosis and autophagy. Importantly, we discuss how these non-apoptotic cell deaths could be targeted as a promising therapeutic strategy for the treatment of drug-resistant melanoma. This review provides a comprehensive overview of non-apoptotic processes and gathers recent experimental evidence that will guide future research and eventually the creation of treatment strategies to combat drug resistance in melanoma. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) describes a heterogeneous group of human neoplasms of the head and neck with high rates of morbidity and mortality, constituting about 3% of all cancers and ~1.5% of all cancer deaths. HNSCC constituted the seventh most prevalent human malignancy and the most common human cancer in the world in 2020, according to multi-population observations conducted by the GLOBOCAN group. Since approximately 60–70% of patients present with stage III/IV neoplastic disease, HNSCC is still one of the leading causes of death in cancer patients worldwide, with an overall survival rate that is too low, not exceeding 40–60% of these patients. Despite the application of newer surgical techniques and the implementation of modern combined oncological treatment, the disease often follows a fatal course due to frequent nodal metastases and local neoplastic recurrences. The role of micronutrients in the initiation, development, and progression of HNSCC has been the subject of considerable research. Of particular interest has been vitamin D, the pleiotropic biologically active fat-soluble family of secosteroids (vitamin-D-like steroids), which constitutes a key regulator of bone, calcium, and phosphate homeostasis, as well as carcinogenesis and the further development of various neoplasms. Considerable evidence suggests that vitamin D plays a key role in cellular proliferation, angiogenesis, immunity, and cellular metabolism. A number of basic science, clinical, and epidemiological studies indicate that vitamin D has multidirectional biological effects and influences anti-cancer intracellular mechanisms and cancer risk, and that vitamin D dietary supplements have various prophylactic benefits. In the 20th century, it was reported that vitamin D may play various roles in the protection and regulation of normal cellular phenotypes and in cancer prevention and adjunctive therapy in various human neoplasms, including HNSCC, by regulating a number of intracellular mechanisms, including control of tumour cell expansion and differentiation, apoptosis, intercellular interactions, angio- and lymphogenesis, immune function, and tumour invasion. These regulatory properties mainly occur indirectly via epigenetic and transcriptional changes regulating the function of transcription factors, chromatin modifiers, non-coding RNA (ncRNAs), and microRNAs (miRs) through protein-protein interactions and signalling pathways. In this way, calcitriol enhances intercellular communication in cancer biology, restores the connection with the extracellular matrix, and promotes the epithelial phenotype; it thus counteracts the tumour-associated detachment from the extracellular matrix and inhibits the formation of metastases. Furthermore, the confirmation that the vitamin D receptor (VDR) is present in many human tissues confirmed the physiopathological significance of vitamin D in various human tumours. Recent studies indicate quantitative associations between exposure to vitamin D and the incidence of HNC, i.e., cancer risk assessment included circulating calcidiol plasma/serum concentrations, vitamin D intake, the presence of the VDR gene polymorphism, and genes involved in the vitamin D metabolism pathway. Moreover, the chemopreventive efficacy of vitamin D in precancerous lesions of the head and neck and their role as predictors of mortality, survival, and recurrence of head and neck cancer are also widely discussed. As such, it may be considered a promising potential anti-cancer agent for developing innovative methods of targeted therapy. The proposed review discusses in detail the mechanisms regulating the relationship between vitamin D and HNSCC. It also provides an overview of the current literature, including key opinion-forming systematic reviews as well as epidemiological, prospective, longitudinal, cross-sectional, and interventional studies based on in vitro and animal models of HNSCC, all of which are accessible via the PubMed/Medline/EMBASE/Cochrane Library databases. This article presents the data in line with increasing clinical credibility. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for over 3 decades and consist of three isotypes, including PPARa, κ, and βd, that were originally considered key metabolic regulators controlling energy homeostasis in the body. Cancer has become a leading cause of human mortality worldwide, and the role of peroxisome proliferator-activated receptors in cancer is increasingly being investigated, especially the deep molecular mechanisms and effective cancer therapies. Peroxisome proliferator-activated receptors are an important class of lipid sensors and are involved in the regulation of multiple metabolic pathways and cell fate. They can regulate cancer progression in different tissues by activating endogenous or synthetic compounds. This review emphasizes the significance and knowledge of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anti-cancer treatment by summarizing recent research on peroxisome proliferator-activated receptors. In general, peroxisome proliferator-activated receptors either promote or suppress cancer in different types of tumor microenvironments. The emergence of this difference depends on various factors, including peroxisome proliferator-activated receptor type, cancer type, and tumor stage. Simultaneously, the effect of anti-cancer therapy based on drug-targeted PPARs differs or even opposes among the three peroxisome proliferator-activated receptor homotypes and different cancer types. Therefore, the current status and challenges of the use of peroxisome proliferator-activated receptors agonists and antagonists in cancer treatment are further explored in this review. [ABSTRACT FROM AUTHOR]

Adoptive T-cell therapy (ACT) is successfully applied in cancer treatment; however, its efficiency can be limited by a low viability, short persistence time, and loss of functional activity of T-cells after adoptive transfer. The search for novel immunomodulators that can improve the viability, expansion, and functions of T-cells after their infusion with the minimal side effects could contribute to the development of more efficient and safe ACT strategies. Recombinant human cyclophilin A (rhCypA) is of particular interest in this respect, as it exhibits pleiotropic immunomodulatory activity and stimulates both innate and adaptive anti-tumor immunity. Here, we evaluated the effect of rhCypA on the efficacy of ACT in the mouse EL4 lymphoma model. Lymphocytes from transgenic 1D1a mice with an inborn pool of EL4-specific T-cells were used as a source of tumor-specific T-cells for ACT. In models of immunocompetent and immunodeficient transgenic mice, the course (3 days) rhCypA administration was shown to significantly stimulate EL4 rejection and prolong the overall survival of tumor-bearing mice after adoptive transfer of lowered doses of transgenic 1D1a cells. Our studies showed that rhCypA significantly improved the efficacy of ACT by enhancing the effector functions of tumor-specific cytotoxic T-cells. These findings open up the prospects for the development of innovative strategies of adoptive T-cell immunotherapy for cancer using rhCypA as an alternative to existing cytokine therapies. [ABSTRACT FROM AUTHOR]

The balance between anabolism and catabolism is disrupted with aging, with the rate of anabolism being faster than that of catabolism. Therefore, mTOR, whose major function is to enhance anabolism and inhibit catabolism, has become a potential target of inhibition for anti-aging therapy. Interestingly, it was found that the downregulation of the mTOR signaling pathway had a lifespan-extending effect resembling calorie restriction. In addition, the mTOR signaling pathway promotes cell proliferation and has been regarded as a potential anti-cancer target. Rapamycin and rapalogs, such as everolimus, have proven to be effective in preventing certain tumor growth. Here, we reviewed the basic knowledge of mTOR signaling, including both mTORC1 and mTORC2. Then, for anti-aging, we cited a lot of evidence to discuss the role of targeting mTOR and its anti-aging mechanism. For cancer therapy, we also discussed the role of mTOR signaling in different types of cancers, including idiopathic pulmonary fibrosis, tumor immunity, etc. In short, we discussed the research progress and both the advantages and disadvantages of targeting mTOR in anti-aging and anti-cancer therapy. Hopefully, this review may promote more ideas to be generated for developing inhibitors of mTOR signaling to fight cancer and extend lifespan. [ABSTRACT FROM AUTHOR]

Dual drug delivery has become the choice of interest nowadays due to its increased therapeutic efficacy in targeting the tumor site precisely. As quoted in recent literature, it has been known to treat several cancers with an acute course of action. Even so, its use is restricted due to the drug's low pharmacological activity, which leads to poor bioavailability and increases first-pass metabolism. To overcome these issues, a drug delivery system using nanomaterials which would not only encapsulate the drugs of interest but also carry them to the target site of action is needed. Given all these attributes, we have formulated dual drug-loaded nanoliposomes with cisplatin (cis-diamminedichloroplatinum(II) (CDDP)), an effective anti-cancer drug, and diallyl disulfide (DADS), an organosulfur compound derived from garlic. The CDDP and DADS-loaded nanoliposomes (Lipo-CDDP/DADS) exhibited better physical characteristics such as size, zeta potential, polydispersity index, spherical shape, optimal stability, and satisfactory encapsulation percentage. The in vitro anti-cancer activity against MDA-MB-231 and A549 cell lines revealed that Lipo-CDDP/DADS showed significant efficacy against the cancer cell lines, depicted through cell nucleus staining. We conclude that Lipo-CDDP/DADS hold exceptional pharmacological properties with better anti-cancer activity and would serve as a promising formulation to treat various cancers. [ABSTRACT FROM AUTHOR]

A leading cancer diagnosis in women worldwide is cervical cancer, with current treatments all posing a risk of serious side effects. Less toxic, but effective treatments are sought after. Aloe vera (barbadensis miller), known for its beneficial properties, has been studied for cancer treatment. While aloe gel has been shown to exhibit anti-cancer activity, it cannot form a hydrogel alone. Therefore, an interpenetrating network comprising alginate blended with aloe was examined as a cervical cancer treatment. We hypothesized the antioxidant properties of aloe gel would decrease cancer cell viability while the alginate hydrogel would improve mucoadhesion. We further hypothesized the antioxidant activity of aloe gel would induce cancer cell death at levels similar to common chemotherapeutics, and aimed to determine if these chemotherapeutic behaviors are constructive or destructive. Material and adhesive properties, drug encapsulation, and cancer cell viability were investigated and validated. The effect of aloe-alginate hydrogels on cervical cancer cell viability was not significantly different compared to aloe-blends containing doxorubicin (DOX), indicating that the aloe alone decreased cancer cell viability rendering the additional cytotoxic therapeutic not impactful as an adjuvant therapy. This study provides insight into the potential of natural biopolymers for treating cervical cancer without systemic toxic compounds. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients' quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM. [ABSTRACT FROM AUTHOR]

The rapid evolution of anti-cancer therapy (including chemotherapy, targeted therapy, and immunotherapy) in recent years has led to a more favorable efficacy and safety profile for a growing cancer population, and the improvement of overall survival and reduction of morbidity for many cancers. Anti-cancer therapy improves outcomes for cancer patients; however, many classes of anti-cancer therapy have been implicated in the induction of bullous dermatologic adverse events (DAE), leading to reduced patient quality of life and in some cases discontinuation of life-prolonging or palliative therapy. Timely and effective management of adverse events is critical for reducing treatment interruptions and preserving an anti-tumor effect. Bullous DAE may be limited to the skin or have systemic involvement with greater risk of morbidity and mortality. We present the epidemiology, diagnosis, pathogenesis, and management of bullous DAE secondary to anti-cancer therapies to enable clinicians to optimize management for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The application of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer therapy has been a widely studied topic for almost four decades. This review summarizes the information about the role of chronic inflammation in the process of carcinogenesis and the evidence regarding the anti-cancer activity of the most frequently used NSAIDs. Despite the promising results of NSAIDs, the possibilities of the practical application of this group of drugs in chemoprevention and cancer therapies on a clinical basis are still impossible due to individual side effects. The main concern is their gastrointestinal toxicity. For this reason, several strategies are still under investigation to reduce toxicity and improve the efficacy of NSAIDs. In this review, we emphasize the effectiveness of combinations of NSAIDs with chemotherapeutic drugs in in vitro and in vivo models as well as in clinical trials. We also present new concepts based on the molecular hybridization of anti-inflammatory drugs with other biologically active molecules, such as phospholipids and terpenes, as solutions for reducing NSAID side effects. The production of derivatives with enhanced biological potentials could also be carried out to target rare types of cancers. Therefore, this manuscript provides new insight into the possibilities of re-purposing NSAIDs for new, outside-the-current-scope applications. Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a widespread cancer of the digestive system that has two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). In the diverse range of cancer therapy schemes, the side effects of conventional treatments remain an urgent challenge to be addressed. Therefore, the pursuit of novel drugs with multiple targets, good efficacy, low side effects, and low cost has become a hot research topic in anticancer therapy. Based on this, epigenetics offers an attractive target for the treatment of esophageal cancer, where major mechanisms such as DNA methylation, histone modifications, noncoding RNA regulation, chromatin remodelling and nucleosome localization offer new opportunities for the prevention and treatment of esophageal cancer. Recently, research on epigenetics has remained at a high level of enthusiasm, focusing mainly on translating the basic research into the clinical setting and transforming epigenetic alterations into targets for cancer screening and detection in the clinic. With the increasing emergence of tumour epigenetic markers and antitumor epigenetic drugs, there are also more possibilities for anti-esophageal cancer treatment. This paper focuses on esophageal cancer and epigenetic modifications, with the aim of unravelling the close link between them to facilitate precise and personalized treatment of esophageal cancer. [ABSTRACT FROM AUTHOR]

Anti-cancer therapy based on oncolytic viruses (OVs) is a targeted approach that takes advantage of OVs’ ability to selectively infect and replicate in tumor cells, activate the host immune response, and destroy malignant cells over healthy ones. Vesicular stomatitis virus (VSV) is known for its wide range of advantages: a lack of pre-existing immunity, a genome that is easily amenable to manipulation, and rapid growth to high titers in a broad range of cell lines, to name a few. VSV-induced tumor immunity can be enhanced by the delivery of immunostimulatory cytokines. The targeted cytokine delivery to tumors avoids the significant toxicity associated with systemic delivery while also boosting the immune response. To demonstrate this enhanced effect on both tumor growth and survival, a novel recombinant VSV (rVSV)-mIL12-mGMCSF, co-expressing mouse IL-12 (interleukin-12) and GM-CSF (granulocyte-macrophage colony-stimulating factor), was tested alongside rVSV-dM51-GFP (rVSV-GFP) that was injected intratumorally in a syngeneic in vivo C57BL/6 mouse model infused subcutaneously with B16-F10 melanoma cells. The pilot study tested the effect of two viral injections 4 days apart and demonstrated that treatment with the two rVSVs resulted in partial inhibition of tumor growth (TGII of around 40%) and an increased survival rate in animals from the treatment groups. The effect of the two VSVs on immune cell populations will be investigated in future in vivo studies with an optimized experimental design with multiple higher viral doses, as a lack of this information presents a limitation of this study.