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Breast cancer is one of the most prevalent malignancies among women. Enhancing the prognosis is an effective approach to enhance the survival rate of breast cancer. Cuproptosis, a copper-dependent programmed cell death process, has been associated with patient prognosis. Inducing cuproptosis is a promising approach for therapy. However, there is currently no anti-breast cancer drug that induces cuproptosis. In this study, we repositioned the clinical drug fluphenazine as a potential agent for breast cancer treatment by inducing cuproptosis. Firstly, we utilized the Cancer Genome Atlas (TCGA) database and Connectivity Map (CMap) database to identify 22 potential compounds with anti-breast cancer activity through inducing cuproptosis. Subsequently, our findings demonstrated that fluphenazine effectively suppressed the viability of MCF-7 cells. Fluphenazine also significantly inhibited the viability of triple negative breast cancer cells MDA-MB-453 and MDA-MB-231. Furthermore, our study revealed that fluphenazine significantly down-regulated the expression of potential prognostic biomarkers associated with cuproptosis, increased copper ion levels, and reduced intracellular pyruvate accumulation. Additionally, it up-regulated the expression of FDX1 at both the mRNA and protein levels, which has been reported to play a crucial role in the induction of cuproptosis. These findings suggest that fluphenazine has the potential to be used as an anti-breast cancer drug by inducing cuproptosis. Therefore, this research provides an insight for the development of novel cuproptosis-dependent anti-cancer agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The treatment efficacy of anticancer drugs in complex physiological environments is still restricted by multi-drug resistance. To overcome this issue, a nanodrug system of HA-SS@CuS@ZIF-8@TPZ&TBMACN (HSCZTT) that breaks through the detoxification barrier for tirapazamine (TPZ) delivery was developed in this manuscript. In addition to the photothermal effect aroused by CuS in HSCZTT, which can damage tumour cells, TBMACN with photostable fluorescence in the aggregate state can also generate sufficient reactive oxygen species (ROS) to destroy tumour cells. The continuous consumption of oxygen in PDT aggravates the hypoxic environment of tumours, which further activates the TPZ released in the acidic microenvironment of the tumour to achieve apoptosis of the tumour cells. The HSCZTT can not only target the CD44 receptor overexpressed on the surface of the cancer cell, but can also effectively consume a large amount of glutathione (GSH) through the disulphide bond-modified hyaluronic acid, which serves as a targeted disulphide bond, interfering with the detoxification barrier. Our finding presents a rational strategy to overcome multidrug resistance for the improved efficacy of anticancer drugs by the targeting of Hyaluronic acid (HA), release of the drug by the acid response of ZIF-8, breakthrough of the detoxification barrier, precise positioning of the drug release and combined treatment with phototherapy and hypoxia-activated chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Research progress from mainly over the last five years is described for a multidisciplinary collaborative program project directed toward the discovery of potential anticancer agents from a broad range of taxonomically defined organisms. Selected lead compounds with potential as new antitumor agents that are representative of considerable structural diversity have continued to be obtained from each of tropical plants, terrestrial and aquatic cyanobacteria, and filamentous fungi. Recently, a new focus has been on the investigation of the constituents of U.S. lichens and their fungal mycobionts. A medicinal chemistry and pharmacokinetics component of the project has optimized structurally selected lead natural products, leading to enhanced cytotoxic potencies against selected cancer cell lines. Biological testing has shown several compounds to have in vivo activity, and relevant preliminary structure-activity relationship and mechanism of action studies have been performed. Several promising lead compounds worthy of further investigation have been identified from the most recent collaborative work performed.

PHY34 is a synthetic small molecule, inspired by a compound naturally occurring in tropical plants of the Phyllanthus genus. PHY34 was developed to have potent in vitro and in vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, PHY34 induced apoptosis in ovarian cancer cells by late-stage autophagy inhibition. Furthermore, PHY34 significantly reduced tumor burden in a xenograft model of ovarian cancer. In order to identify its molecular target/s, we undertook an unbiased approach utilizing mass spectrometry-based chemoproteomics. Protein targets from the nucleocytoplasmic transport pathway were identified from the pulldown assay with the cellular apoptosis susceptibility (CAS) protein, also known as CSE1L, representing a likely candidate protein. A tumor microarray confirmed data from mRNA expression data in public databases that CAS expression was elevated in HGSOC and correlated with worse clinical outcomes. Overexpression of CAS reduced PHY34 induced apoptosis in ovarian cancer cells based on PARP cleavage and Annexin V staining. Compounds with a diphyllin structure similar to PHY34 have been shown to inhibit the ATP6V0A2 subunit of V(vacuolar)-ATPase. Therefore, ATP6V0A2 wild-type and ATP6V0A2 V823 mutant cell lines were tested with PHY34, and it was able to induce cell death in the wild-type at 246 pM while the mutant cells were resistant up to 55.46 nM. Overall, our data demonstrate that PHY34 is a promising small molecule for cancer therapy that targets the ATP6V0A2 subunit to induce autophagy inhibition while interacting with CAS and altering nuclear localization of proteins., (© 2022. The Author(s).)

Background: The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies., Result: In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect., Conclusion: The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy., (© 2021. The Author(s).)

Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency ( η = 37%), desired cytocompatibility, and excellent synergistic therapeutic efficacy. The proposed nanoplatform not only extends the application scope of melanin materials with AIE-active PSs, but also offers useful insights into developing multistimulus as well as multimodal synergistic tumor treatment.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of blood cancers arising in lymphoid tissues that commonly effects both humans and dogs. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the symmetric di-methylation of arginine residues, is frequently overexpressed and dysregulated in both human solid and hematologic malignancies. In human lymphoma, PRMT5 is a known driver of malignant transformation and oncogenesis, however, the expression and role of PRMT5 in canine lymphoma has not been explored. To explore canine lymphoma as a useful comparison to human lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine lymphoma tissue microarrays, primary lymphoid biopsies, and canine lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility and whole-transcriptome changes in canine lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued use of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.B. has received research funding from Prelude Therapeutics, K.V. and P.S. are employees of Prelude Therapeutics, and V.E.V. was an employee of VDx Veterinary Diagnostics. No other conflicts of interest are relevant to this reported work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Colorectal cancer (CRC) is an aggressive malignancy with very limited therapeutic approaches. Drug resistance develops as a frequent characteristic in many patients with CRC, which leads to a decrease in the therapeutic efficacy of anticancer agents. Our previous evidences showed that bound polyphenol from millet bran (BPIS) possesses the potential of inhibiting cancer cell proliferation, and its main anticancer components are ferulic acid (FA) and p-coumaric acid (p-CA). In the present study, we found that BPIS significantly increases the sensitivity of human drug-resistant CRC cell line to oxaliplatin (OXA), a commonly used chemotherapy drug against CRC. Mechanistically, we indicated that BPIS significantly impairs the expression of a gene encoding multidrug resistance protein 1 (MDR1), a well-known permeability glycoprotein (P-gp), by preventing ganglioside GM3 catabolism. Neuraminidase 3 (NEU3) is a key enzyme catalyzing the conversion of ganglioside GM3 to ceramide trihexosides (Gb3), whose expression is increased in drug-resistant HCT-116/L cells. BPIS treatment increased GM3 level, but reduced Gb3 and P-gp levels by inhibiting NEU3 expression, which subsequently boosted the chemotherapy sensitivity of drug-resistant HCT-116/L cells to OXA. These findings reveal that BPIS increases the chemo-sensitivity by remodeling NEU3-mediated ganglioside GM3 catabolism, and it may be applied as a novel drug for facilitating the effectiveness of chemotherapeutic agents in CRC.

Tumor microenvironment (TME)-induced drug delivery technology is a promising strategy for improving low drug accumulation efficiency, short blood circulation and weak therapeutic effect. In this work, a dual-responsive (reduction- and pH-responsive) polyprodrug nanoreactor based on β-cyclodextrin (β-CD) was constructed for combinational chemotherapy. Specifically, the dual-responsive star polymeric prodrug was synthesized by atom transfer radical polymerization (ATRP) based on a starburst initiator of β-CD-Br. The obtained polyprodrug contained a hydrophilic chain of poly-(ethylene glycol) methyl ether methacrylate (POEGMA) and a hydrophobic part of camptothecin (CPT) prodrug and poly[2-(diisopropylamino)ethyl methacrylate] (PDPA), denoted as β-CD-PDPA-POEGMA-PCPT (CCDO for short). The obtained CCDO could form stable unimolecular micelles, which could be efficiently internalized by cancer cells. To enhance the curative effect, the anticancer agent doxorubicin (DOX) could be encapsulated into the hydrophobic cavity of the CCDO by hydrophobic-hydrophobic interaction. In vitro drug release studies showed that the obtained CCDO/DOX micelles controlled the release of active CPT and DOX occurring in a reductive environment and at low pH. In vitro cytotoxicity results suggested that the anticancer efficacy of dual-responsive CCDO/DOX micelles was superior to that of CCDO micelles. In addition, in vivo results verified good blood compatibility of the unimolecular micelles. This integrated dual-responsive drug delivery system may solve the low drug loading and poor controlled release problems found in traditional polymer-based drug carriers, providing an innovative and promising route for cancer therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Polymeric prodrug based on therapeutic nanomedicine has demonstrated great promise for effective tumor growth inhibition, however, the drawbacks of low drug-loading and weak micellar stability limit its application for clinical cancer therapy. Herein, a reduction-responsive starburst block copolymer prodrug CCP [β-cyclodextrin (β-CD)-PCPT XX -POEGMA, XX: SS or CC] has been developed for cancer therapy. And CCP is composed of β-CD-Br core with multiple reactive sites, as well as a diblock copolymer containing hydrophobic polymerized camptothecin (PCPT) prodrug chain and hydrophilic poly[(ethylene glycol) methyl ether methacrylate] (OEGMA) chain. A family of CCP polymeric prodrugs with different drug loading contents (up to 25%) and various sizes of unimolecular micelles (UMs) (around 30 nm) were obtained by adjusting the block ratio of PCPT XX and POEGMA. On account of the amphiphilic structure feature, CPP could take shape water-soluble UMs in aqueous medium with excellent micellar stability. Under imitatively reductive tumor microenvironment, anticancer drug CPT could rapidly escape from CCP UMs in terms of disulfide bond breakage. However, this behavior is strongly refrained in the physiological environment. In vitro and in vivo outcome confirmed that CCP UMs showed excellent performance of sufficient tumor accumulation, high-efficiency tumor growth inhibition and low-toxicity for healthy tissues. Based on these gratifying therapeutic efficacy, it is believed that as-present starburst prodrug strategy can offer a brand-new insight for high-efficiency therapeutic nanoplatforms for chemotherapy application.

Esophageal cancer (EC) is the 6th leading cause of cancer mortality worldwide with poor prognosis, hence more effective chemotherapeutic drugs for this deadly disease are urgently needed. We previously reported that high expression of Orai1, a store-operated Ca 2+ entry (SOCE) channel, was associated with poor survival rate in EC patients and Orai1-mediated intracellular Ca 2+ oscillations regulated cancer cell proliferation. Previous studies suggested that Orai1-mediated SOCE is a promising target for EC chemotherapy. Here, we evaluated the anti-cancer effect of a novel SOCE inhibitor, RP4010, in cultured EC cells and xenograft models. Compared to other previously reported SOCE channel inhibitors, RP4010 is more potent in blocking SOCE and inhibiting cell proliferation in EC and other cancer cells. Treatment with RP4010 resulted in reduction of intracellular Ca 2+ oscillations, caused cell cycle arrest at G0/G1 phase in vitro, decreased nuclear translocation of nuclear factor kappa B (NF-κB) in vivo and in vitro, and inhibited tumor growth in vivo. Taken together, data demonstrated the therapeutic potential of RP4010 in EC patients via inhibition of SOCE-mediated intracellular Ca 2+ signaling., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

Apigenin (AP), as an anticancer agent, has been widely explored. However, the molecular targets of apigenin on tumor metabolism are unclear. Herein, we found that AP could block cellular glycolysis through restraining the tumor-specific pyruvate kinase M2 (PKM2) activity and expression and further significantly induce anti-colon cancer effects. The IC 50 values of AP against HCT116, HT29, and DLD1 cells were 27.9 ± 2.45, 48.2 ± 3.01 and 89.5 ± 4.89 μM, respectively. Fluorescence spectra and solid-phase AP extraction assays proved that AP could directly bind to PKM2 and markedly inhibit PKM2 activity in vitro and in HCT116 cells. Interestingly, in the presence of d-fructose-1,6-diphosphate (FBP), the inhibitory effect of AP on PKM2 was not reversed, which suggests that AP is a new allosteric inhibitor of PKM2. RT-PCR and Western blot assays showed that AP could ensure a low PKM2/PKM1 ratio in HCT116 cells via blocking the β-catenin/c-Myc/PTBP1 signal pathway. Hence, PKM2 represents a novel potential target of AP against colon cancer.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Chemotherapy is frequently used for gastric cancer treatment. Most patients with advanced gastric cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for cancer relapse following chemotherapy will help design new ways to treat gastric cancer. In this study, we revealed that the residual cancer cells following treatment with chemotherapeutic reagent cisplatin have elevated expression of hedgehog target genes GLI1, GLI2 and PTCH1, suggestive of hedgehog signaling activation. We showed that GLI1 knockdown sensitized gastric cancer cells to CDDP whereas ectopic GLI1 expression decreased the sensitivity. Further analyses indicate elevated GLI1 expression is associated with an increase in tumor sphere formation, side population and cell surface markers for putative cancer stem cells. We have evidence to support that GLI1 is critical for maintenance of putative cancer stem cells through direct regulation of ABCG2. In fact, GLI1 protein was shown to be associated with the promoter fragment of ABCG2 through a Gli-binding consensus site in gastric cancer cells. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, increased drug sensitivity of cancer cells both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance.

Hepatocellular carcinoma, a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Here, we examined the therapeutic efficacy of CCL2-CCR2 axis inhibitors against hepatitis and hepatocellular carcinoma in the miR-122 knockout (a.k.a. KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to hepatocellular carcinoma with age. Therapeutic potential of CCL2-CCR2 axis blockade was determined by treating KO mice with a CCL2-neutralizing antibody (nAb). This immunotherapy suppressed chronic liver inflammation in these mice by reducing the population of CD11 high Gr1 + inflammatory myeloid cells and inhibiting expression of IL6 and TNFα in KO livers. Furthermore, treatment of tumor-bearing KO mice with CCL2 nAb for 8 weeks significantly reduced liver damage, hepatocellular carcinoma incidence, and tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL6, as well as NF-κB, the downstream target of TNFα, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. In addition, CCL2 nAb enhanced hepatic NK-cell cytotoxicity and IFNγ production, which is likely to contribute to the inhibition of tumorigenesis. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and hepatocellular carcinoma. Mol Cancer Ther; 16(2); 312-22. ©2016 AACR., Competing Interests: The authors disclose no conflicts., (©2016 American Association for Cancer Research.)

Recent progress is described in an ongoing collaborative multidisciplinary research project directed towards the purification, structural characterization, chemical modification, and biological evaluation of new potential natural product anticancer agents obtained from a diverse group of organisms, comprising tropical plants, aquatic and terrestrial cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which initial extracts, chromatographic fractions, and purified isolated compounds of these acquisitions are tested. Several promising biologically active lead compounds from each major organism class investigated are described, and these may be seen to be representative of a very wide chemical diversity., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL).

Context: Cardiotoxicity and myelosuppression of etoposide (ETP) limited its clinical application. Targeted drug delivery system could deliver anticancer agents to the target cancerous cells, thus reducing their toxicity., Objective: In this study, folate (FA) was applied for the construction of nanostructured lipid carriers (NLCs), and used for targeted delivery of ETP to tumors overexpresses the FA receptors., Methods: FA-poly (ethylene glycol)-distearoylphosphatidylethanolamine was synthesized. FA decorated and ETP-loaded NLCs (FA-ETP-NLCs) were prepared and the formulation was optimized by Box-Behnken design. Their particle size (PS), zeta potential and drug encapsulation efficiency (EE) was evaluated. In vitro cytotoxicity studies of FA-ETP-NLCs were tested in CT26, SGC7901, NCI-H209 cell lines. In vivo antitumor efficacies of the carriers were evaluated on mice bearing CT26 cells xenografts., Results: The optimum FA-ETP-NLCs formulations had a PS of 120.86 nm. The growth of CT26, SGC790 or NCI-H209 cells in vitro was obviously inhibited. FA-ETP-NLCs also displayed the best antitumor activity than other formulations in vivo., Conclusion: The results demonstrated that FA-ETP-NLCs were efficient in selective delivery to CT26, SGC790 or NCI-H209 cells overexpressing the FA receptors. Also, FA-ETP-NLCs can sufficiently transfer ETP to the cancer cells, enhance the antitumor capacity. Thus, FA-ETP-NLCs could prove to be a superior nanomedicine to achieve tumor therapeutic efficacy.

There is high expectation for significant improvements in cancer patient care after completion of the human genome project in 2003. Through pains-taking analyses of genomic profiles in cancer patients, a number of targetable gene alterations have been discovered, with some leading to novel therapies, such as activating mutations of EGFR, BRAF and ALK gene fusions. As a result, clinical management of cancer through targeted therapy has finally become a reality for a subset of cancers, such as lung adenocarcinomas and melanomas. In this review, we summarize how gene mutation discovery leads to new treatment strategies using non-small cell lung cancer (NSCLC) as an example. We also discuss possible future implications of cancer genome analyses., (Copyright © 2015 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: Epithelioid sarcoma is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it poses a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors (HDACi) exhibit marked antitumor effects in various malignancies. The studies here demonstrate that pan-HDAC inhibitors constitute novel therapeutics versus epithelioid sarcoma. Human ES cells (VAESBJ, HS-ES, Epi-544) were studied in preclinical models to evaluate HDACi effects. Immunoblot and RT-PCR were used to evaluate expression of acetylated tubulin, histones H3/H4, EZH2 upon HDACi. MTS and clonogenic assays were used to assess the impact of HDACi on cell growth. Cell culture assays were used to evaluate the impact of HDACi and EZH2-specific siRNA inhibition on cell-cycle progression and survival. Unbiased gene array analysis was used to identify the impact of HDACi on epithelioid sarcoma gene expression. Xenografts were used to evaluate epithelioid sarcoma tumor growth in response to HDACi. HDAC inhibition increased target protein acetylation and abrogated cell growth and colony formation in epithelioid sarcoma cells. HDACi induced G(2) cell-cycle arrest and marked apoptosis, and reduced tumor growth in xenograft models. HDACi induced widespread gene expression changes, and EZH2 was significantly downregulated. EZH2 knockdown resulted in abrogated cell growth in vitro., Implications: The current study suggests a clinical role for HDACi in human epithelioid sarcoma, which, when combined with EZH2 inhibitors, could serve as a novel therapeutic strategy for epithelioid sarcoma patients. Future investigations targeting specific HDAC isoforms along with EZH2 may potentially maximizing treatment efficacy., (©2015 American Association for Cancer Research.)

Acute myeloid leukemia (AML) is a hematological malignancy with a low survival rate. Curcumin, which is a multi-targeted anticancer agent, has been shown to exert anti‑oxidant, anti‑inflammatory, anti‑mutagenic and anti‑carcinogenic activities. Naringenin is extracted from citrus fruits and exerts anti‑mutagenic and anti‑carcinogenic activities in various types of cancer cells. However, the effects of curcumin and naringenin in combination in AML cells have yet to be studied. The present study aimed to investigate the combination effects of curcumin and naringenin on the viability, cell cycle distribution and apoptosis rate of THP‑1 cells using cell viability assays, flow cytometry, and western blotting. Naringenin enhanced curcumin‑induced apoptosis and cell viability inhibition. In addition, curcumin and naringenin induced cell cycle arrest at S phase and G2/M phase. Numerous pathways, including p53, c‑Jun N‑terminal kinases (JNK), Akt and extracellular signal‑regulated kinases (ERK)1/2 pathways were markedly altered following treatment of THP‑1 cells with curcumin and naringenin. These results indicated that naringenin may enhance curcumin‑induced apoptosis through inhibiting the Akt and ERK pathways, and promoting the JNK and p53 pathways.

Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells. However, the effects of silvestrol on immune function have not been described. We utilized in vitro and in vivo models of EBV-LPD to simultaneously examine the impact of silvestrol on both tumor and normal immune function. We show that silvestrol induces direct anti-tumor activity against EBV-transformed lymphoblastoid cell lines (LCL), with growth inhibition, decreased expression of the EBV oncogene latent membrane protein-1, and inhibition of the downstream AKT, STAT1 and STAT3 signaling pathways. Silvestrol promoted potent indirect anti-tumor effects by preserving expansion of innate and EBV antigen-specific adaptive immune effector subsets capable of effective clearance of LCL tumor targets in autologous co-cultures. In an animal model of spontaneous EBV-LPD, silvestrol demonstrated significant therapeutic activity dependent on the presence of CD8-positive T-cells. These findings establish a novel immune-sparing activity of silvestrol, justifying further exploration in patients with EBV-positive malignancies.

Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL., (© 2015 by The American Society of Hematology.)

Background: It has been reported that the hypermethylation of APAF-1, DAPK-1 and other tumor suppressive genes (TSGs) correlates with progression of renal cell carcinoma and exerts prognostic and diagnostic relevance in renal cell carcinoma. A recent study has confirmed that demethylation regulates the TSGs expression and proliferation of various types of cancer cells. The present study was to recognize a potential anti-tumor effect of 5-aza-2'-deoxycytidine (DAC), a demethylation agent., Methods: We evaluated the DNA demethylation by DAC in human renal carcinoma cells and determined the synergism of the demethylation with the toxicity of Cisplatin (CDDP), which is a commonly utilized anti-tumor agent for renal carcinoma., Results: It was demonstrated that DAC promoted a significant global genomic demethylation and improved APAF-1 expression at both mRNA and protein levels. The DAC treatment deteriorated the CDDP-induced viability decreasing Caki or ACHN cells and synergized the apoptosis induction of CDDP in ACHN cells. The treatment with both DAC and CDDP promoted a significantly higher level of renal carcinoma cell apoptosis than singular DAC or CDDP treatment. The APAF-1 knockdown significantly inhibited the synergism of DAC with the CDDP-induced apoptosis in ACHN cells., Conclusions: The present study confirmed that DAC demethylated the CpGs, particularly APAF-1 in renal carcinoma cells, and that the demethylation synergized the cytotoxity of CDDP in renal carcinoma cells via enhancing the CDDP-induced apoptosis.

Modifying positive surface charge and reducing bulk size of nanoparticles has been proven beneficial to cancer cellular delivery, but meanwhile results in fast clearance and unspecific distribution in body after intravenous injection. How to balance these problems is still a challenge to construct an ideal nano-scaled drug delivery system in cancer treatment. Herein, we developed a multistage drug delivery system to enhance anticancer efficacy of curcumin (CUR), which could intelligently alter its size and surface charge after long-circulation and extravasation from leaky blood vessels at tumor sites. This micellar system was constructed by amphiphilic and pH-sensitive methoxy poly(ethylene glycol)-poly(lactide)-poly(β-amino ester) (MPEG-PLA-PAE) copolymers. As compared with MPEG-PLA micelles, MPEG-PLA-PAE micelles displayed several advantageous characteristics for drug delivery and treatment. We found that CUR-loaded MPEG-PLA-PAE micelles remained stable in murine plasma at 37 °C even with high drug loading. More interestingly, when the media pH decreased from 7.4 to 5.5, the micelles shrank from 171.0 nm to 22.6 nm and their surface charge increased to 24.8 mV meanwhile, which resulted in the significantly improved cell uptake of CUR by human breast cancer MCF-7 cells. Using indocyanine green (ICG) as a fluorescence probe, it was observed that MPEG-PLA-PAE micelles experienced longer circulation than MPEG-PLA micelles followed by accumulation at tumors with stronger fluorescence intensity. Consequently, MPEG-PLA-PAE micelles achieved enhanced cancer growth inhibition of 65.6% in vivo. All these findings demonstrated the potential of size/charge-changing MPEG-PLA-PAE micelles as a promising drug delivery system for tumor-targeted therapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavir's effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties.

The hollow fiber assay (HFA) is a drug discovery tool to aid investigators in the prioritization of lead compounds identified by in vitro testing for further development in animal models of disease. In the HFA, cells are cultured in hollow fibers containing pores of a diameter (500 kDa) large enough for proteins and other macromolecules to enter, but too small for the cells to escape. The fibers are filled with cells, sealed and placed in the peritoneal cavity of immunodeficient mice. The mice undergo a predetermined treatment regimen after which the fibers are retrieved and the cells evaluated for activity of a target relevant to the disease modeled. The HFA combines advantages of both in vitro and in vivo assay systems. It uses the same cell lines used in culture systems, is a rapid assay, and requires fewer animals and less test substance than conventional xenograft systems. Like traditional in vivo assays, the test substance is evaluated in a live animal, which affords an initial assessment of associated toxicity and pharmacokinetic properties of the test substance.

Bioassay-guided fractionation was conducted on a chloroform-soluble extract of the aerial parts of Piper sarmentosum collected in Vietnam, monitored by a mitochondrial transmembrane potential assay using HT-29 human colon cancer cells. This led to the isolation of four new C-benzylated dihydroflavones, sarmentosumins A-D (1-4), as well as 14 known compounds. The structures of the new compounds were elucidated on the basis of spectroscopic data interpretation. Among these compounds, 1-4 as well as five known C-benzylated dihydroflavones (5-9) and a piperamide, pipercallosine (11), were found to induce apoptosis in HT-29 cells by moderately reducing the mitochondrial transmembrane potential (ΔΨm), with ED50 values ranging from 1.6 to 13.6 μM. Furthermore, 7-methoxydichamanetin (8) and pinocembrin (10) exhibited proteasome inhibitory activities in a human 20S proteasome bioassay with IC50 values of 3.45±0.18 and 2.87±0.26 μM, respectively. This is the first time that C-benzylated dihydroflavones have been reported to demonstrate an apoptotic effect associated with disruption of the mitochondrial transmembrane potential.

The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-α), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-α and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-α from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-α was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform., (Published by Elsevier B.V.)

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote humoral immune responses but also induces a distinct disease-specific toxicity of tumor flare and cytokine release. These CLL-specific events result from increased expression of costimulatory molecules on B cells. Here we demonstrate that lenalidomide activation of CLL cells depends on the phosphatidylinositol 3-kinase p110δ (PI3K-δ) pathway. Inhibition of PI3K-δ signaling by the PI3K-δ-inhibiting drug, CAL-101, or by siRNA knockdown of p110δ, abrogates CLL cell activation, costimulatory molecule expression, and vascular endothelial growth factor and basic fibroblast growth factor gene expression that is induced by lenalidomide. In addition, CAL-101 attenuates lenalidomide-mediated increases in immunoglobulin M production by normal B cells. Collectively, these data demonstrate the importance of PI3K-δ signaling for lenalidomide immune modulation. These findings may guide development of strategies for the treatment of CLL that combine lenalidomide with CAL-101, with other inhibitors of the PI3K-δ pathway, or with other agents that target downstream kinases of this signaling pathway.

Chronic lymphocytic leukemia (CLL) is an incurable progressive disease for which new therapies are required. Therapy with monoclonal antibodies (mAbs) has improved the outcome of patients with CLL, making further investigation of novel antibodies directed against alternative and specific targets on B cells an important area of translational research. We now describe functional properties of an antagonistic humanized mAb to CD74, milatuzumab, showing that milatuzumab combined with a crosslinking antibody induces cytotoxicity in vitro in CLL cells in a caspase- and stromal-independent manner associated with aggregation of CD74 on the cell surface. Furthermore, incorporation of milatuzumab into an immunoliposome induces even more of a cytotoxic response than in vitro crosslinking, representing a novel therapeutic formulation for this mAb. Based on these data, future development of the milatuzumab-immunoliposome formulation as a therapeutic agent for CLL is warranted.

Purpose: Despite the progress that has been made in the treatment of mantle cell lymphoma (MCL), all patients invariably relapse with the currently available therapies. Because of the absence of curative therapy for MCL, we explored FTY720 as a novel agent against MCL., Experimental Design: The cytotoxic effect of FTY720 in primary MCL tumor cells and cell lines were evaluated in vitro. The effects of FTY720 on caspase activation, generation of reactive oxygen species, and modulation of Cyclin D1 and Akt, which are implied in the pathogenesis of MCL, were investigated. The in vivo efficacy of FTY720 was evaluated in a Jeko-severe combined immunodeficient xenograft model of human MCL., Results: FTY720 mediated time- and dose-dependent cytotoxicity in primary MCL tumor cells and MCL cell lines in vitro. FTY720-induced cytotoxicity occured independent of caspase activation but dependent on the generation of ROS in MCL. In addition, FTY720 treatment resulted in the time-dependent downmodulation of Cyclin D1 and accumulation of cells in G(0)-G(1) and G(2)-M phases of the cell cycle with concomitant decrease in S-phase entry. Furthermore, concentrations of FTY720 that induced cytotoxicity led to decreased phospho-Akt in primary MCL cells and cell lines. Most importantly, the in vivo therapeutic activity of FTY720 was shown in severe combined immunodeficient mice engrafted with the Jeko MCL cell line., Conclusions: These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of FTY720 in clinical trials to treat patients with MCL., ((c) 2010 AACR.)

Osthol (osthole), known as a neuroprotective drug, has shown potent anticancer activity. However, the potential clinical application of osthol is limited due to its low water solubility and low bioavailability. Polybutyl cyanoacrylate (PBCA) has been widely used to improve the solubility of drugs with poor water solubility. In this study, an orthogonal experimental design (OED) was applied to design the preparation process of PBCA nanoparticles (NPs). Then, nanoparticles were prepared and evaluated in terms of physicochemical properties, in vitro release, and cellular uptake, etc. Further, the anti-cancer activity of osthol-PBCA NPs was demonstrated in SH-SY5Y cells. The pharmacokinetics and area under the curve (AUC) were investigated. The obtained osthol-NPs presented a spherical shape with a particle size of 110 ± 6.7 nm, a polydispersity index (PDI) of 0.126, and a zeta potential of −13 ± 0.32 mV. Compared with the free osthol, the drugs in osthol-NPs presented better stability and sustained release pattern activity. In vitro analysis using SH-SY5Y neuroblastoma cells showed that osthol-loaded nanoparticles displayed a significantly enhanced intracellular absorption process (three times) and cytotoxicity compared with free osthol (p < 0.05, increased 10–20%). The in vivo pharmacokinetic study revealed that the AUC of osthol-NPs was 3.3-fold higher than that of free osthol. In conclusion, osthol-PBCA NPs can enhance the bioactivity of osthol, being proposed as a novel, promising vehicle for drug delivery. [ABSTRACT FROM AUTHOR]

Simple Summary: Estrogen receptors α (ERα) and β (ERβ) show distinct contributions to tumor initiation and progression. Given that ERβ mainly functions as a "tumor suppressor", activation of ERβ using its specific agonist should be able to inhibit tumor progression. In this study, we show that a newly developed ERβ agonist, OSU-ERb-12, can not only impede ovarian cancer cell expansion and tumor growth but also reduce the cancer stem cell (CSC) population. OSU-ERb-12 could inhibit epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells by increasing Snail expression, thereby, blocking EMT-mediated cancer cell dedifferentiation. We also found that OSU-ERb-12 inhibits ovarian cancer expansion in an ERα-independent manner while limiting the CSC population in an ERα-dependent manner. Taken together, our data suggest that the newly developed ERβ agonist OSU-ERb-12 can be used not only to hinder tumor growth but also has the potential to prevent tumor relapse and metastasis by depleting CSCs. Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

We reported a kinetic control over supramolecular hydrogelation and more importantly over the anticancer properties of taxol. [ABSTRACT FROM AUTHOR]

• Gut microbiota dysbiosis influences the progression of breast cancer. • Less Lactobacillus may be beneficial for anti-tumor immune responses in the TME. • Lactobacillus-mediated pro-tumor effect is related to the production of lactic acid. • High concentration of lactic acid might diminish the anti-tumor immunity. Studies have proven that gut microbiota dysbiosis may influence the carcinogenesis and outcomes of multiple cancers. However, it is still unclear whether gut microbiota dysbiosis affect the progression of breast cancer, especially triple-negative breast cancer. In the present study, by using gut microbiota dysbiosis murine model established by treatment of mice with streptomycin, we found Lactobacillus and the metabolite-lactic acid are the pivotal factors for 4T1 tumor progression. In fact, streptomycin-treated mice exhibited slower tumor growth, in parallel with less abundance of Lactobacillus in the gut. Supplementation with Lactobacillus resulted in a rapid tumor growth, following a decrease in the expression of mRNAs for anti-tumor-related factors but an increase in the M2 polarization. The elevated percentages of IFN-γ-producing CD4+T cells and CD8+T cells in the tumor microenvironment of streptomycin-treated tumor-bearing mice may be vanished by supplementation of Lactobacillus. It seems likely that lactobacillus-mediated pro-tumor effect is related to the production of lactic acid. A decrease in the levels of lactic acid in the cecal feces and tumor tissues were observed in streptomycin-treated tumor bearing mice. However, supplementation of Lactobacillus can restore streptomycin-reduced concentration of lactic acid in the tumor tissues, suggesting that gut Lactobacillus are the source of lactic acid. Bioinformatics analysis result suggests high concentration of lactic acid in tumor sites may be related to the diminished anti-tumor immunity in the TME. This study reveals a correlation between gut Lactobacillus and tumor progression in a murine 4T1 tumor model, providing experimental evidence for clinical treatment of breast cancer. [ABSTRACT FROM AUTHOR]