Current Cancer Drug Targets - Volume 19, Issue 7, 2019

Heat shock factor 1 (HSF1) was discovered in 1984 as the master regulator of the heat shock response. In this classical role, HSF1 is activated following cellular stresses such as heat shock that ultimately lead to HSF1-mediated expression of heat shock proteins to protect the proteome and survive these acute stresses. However, it is now becoming clear that HSF1 also plays a significant role in several diseases, perhaps none more prominent than cancer. HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others. Because of these functions, and others, of HSF1, it has been investigated as a biomarker for patient outcomes in multiple cancer types. HSF1 expression alone was predictive for patient outcomes in multiple cancer types but in other instances, markers for HSF1 activity were more predictive. Clearly, further work is needed to tease out which markers are most representative of the tumor promoting effects of HSF1. Additionally, there have been several attempts at developing small molecule inhibitors to reduce HSF1 activity. All of these HSF1 inhibitors are still in preclinical models but have shown varying levels of efficacy at suppressing tumor growth. The growth of research related to HSF1 in cancer has been enormous over the last decade with many new functions of HSF1 discovered along the way. In order for these discoveries to reach clinical impact, further development of HSF1 as a biomarker or therapeutic target needs to be continued.

Cancer is characterized by high mortality and low curability. Recent studies have shown that the mechanism of tumor resistance involves not only endogenous changes to tumor cells, but also to the tumor microenvironment (TME), which provides the necessary conditions for the growth, invasion, and metastasis of cancer cells, akin to Stephen Paget’s hypothesis of “seed and soil.” Hence, the TME is a significant target for cancer therapy via nanoparticles, which can carry different kinds of drugs targeting different types or stages of tumors. The key step of nanotherapy is the achievement of accurate active or passive targeting to trigger drugs precisely at tumor cells, with less toxicity and fewer side effects. With deepened understanding of the tumor microenvironment and rapid development of the nanomaterial industry, the mechanisms of nanotherapy could be individualized according to the specific TME characteristics, including low pH, cancer-associated fibroblasts (CAFs), and increased expression of metalloproteinase. However, some abnormal features of the TME limit drugs from reaching all tumor cells in lethal concentrations, and the characteristics of tumors vary in numerous ways, resulting in great challenges for the clinical application of nanotherapy. In this review, we discuss the essential role of the tumor microenvironment in the genesis and development of tumors, as well as the measures required to improve the therapeutic effects of tumor microenvironment-targeting nanoparticles and ways to reduce damage to normal tissue.

Colorectal cancer is a heterogeneous group of diseases that result from the accumulation of different sets of genomic alterations, together with epigenomic alterations, and it is influenced by tumor–host interactions, leading to tumor cell growth and glycolytic imbalances. This review summarizes recent findings that involve multiple signaling molecules and downstream genes in the dysregulated glycolytic pathway. This paper further discusses the role of the dysregulated glycolytic pathway in the tumor initiation, progression and the concomitant systemic immunosuppression commonly observed in colorectal cancer patients. Moreover, the relationship between colorectal cancer cells and T cells, especially CD8+ T cells, is discussed, while different aspects of metabolic pathway regulation in cancer cell proliferation are comprehensively defined. Furthermore, this study elaborates on metabolism in colorectal cancer, specifically key metabolic modulators together with regulators, glycolytic enzymes, and glucose deprivation induced by tumor cells and how they inhibit T-cell glycolysis and immunogenic functions. Moreover, metabolic pathways that are integral to T cell function, differentiation, and activation are described. Selective metabolic inhibitors or immunemodulation agents targeting these pathways may be clinically useful to increase effector T cell responses for colorectal cancer treatment. However, there is a need to identify specific antigens using a cancer patient-personalized approach and combination strategies with other therapeutic agents to effectively target tumor metabolic pathways.

Background: Diarrhea is a severe side effect of irinotecan, a pro-drug of SN-38 used for the treatment of many types of cancers. Pre-clinical and clinical studies showed that decreasing the colonic exposure of SN-38 can mitigate irinotecan-induced diarrhea. Objective: The purpose of this study is to evaluate the anti-diarrhea potential of Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese herbal formula, against irinotecan-induced diarrhea by determining if and how XCHT alters the disposition of SN-38. Methods: LC-MS/MS was used to quantify the concentrations of irinotecan and its major metabolites (i.e., SN-38, SN-38G). An Intestinal perfusion model was used to determine the effect of XCHT on the biliary and intestinal secretions of irinotecan, SN-38, and SN-38G. Pharmacokinetic (PK) studies were performed to determine the impact of XCHT on the blood and fecal concentrations of irinotecan, SN-38, and SN-38G. Results: The results showed that XCHT significantly inhibits both biliary and intestinal excretions of irinotecan, SN-38, and SN-38G (range: 35% to 95%). PK studies revealed that the fecal concentrations of irinotecan and SN-38 were significantly decreased from 818.35 ± 120.2 to 411.74 ± 138.83 μg/g or from 423.95 ± 76.44 to 245.63 ± 56.72 μg/g (p<0.05) by XCHT, respectively, suggesting the colonic exposure of SN-38 is significantly decreased by XCHT. PK studies also showed that the plasma concentrations of irinotecan, SN-38, and SN-38G were not affected by XCHT. Conclusion: In conclusion, XCHT significantly decreased the exposure of SN-38 in the gut without affecting its plasma level, thereby possessing the potential of alleviating irinotecan-induced diarrhea without negatively impacting its therapeutic efficacy.

Background: The clinical pathological features, as well as the cellular mechanisms of miR-195, have not been investigated in thyroid carcinoma. Objective: The aim of this study is to identify the interactions of vascular endothelial growth factor (VEGF), p53 and miR-195 in thyroid carcinoma. The clinical and pathological features of miR-195 were also investigated. Methods: The expression levels of miR-195 were identified in 123 primary thyroid carcinomas, 40 lymph nodes with metastatic papillary thyroid carcinomas and seven non-neoplastic thyroid tissues (controls) as well as two thyroid carcinoma cell lines, B-CPAP (from metastasizing human papillary thyroid carcinoma) and MB-1 (from anaplastic thyroid carcinoma), by the real-time polymerase chain reaction. Using Western blot and immunofluorescence, the effects of exogenous miR-195 on VEGF-A and p53 protein expression levels were examined. Then, cell cycle and apoptosis assays were performed to evaluate the roles of miR-195 in cell cycle progression and apoptosis. Results: The expression of miR-195 was downregulated in majority of the papillary thyroid carcinoma tissue as well as in cells. Introduction of exogenous miR-195 resulted in downregulation of VEGF-A and upregulation of p53 protein expressions. Upregulation of miR-195 in thyroid carcinoma cells resulted in cell cycle arrest. Moreover, we demonstrated that miR-195 inhibits cell cycle progression by induction of apoptosis in the thyroid carcinoma cells. Conclusion: Our findings showed for the first time that miR-195 acts as a tumour suppressor and regulates cell cycle progression and apoptosis by targeting VEGF-A and p53 in thyroid carcinoma. The current study exhibited that miR-195 might represent a potential therapeutic target for patients with thyroid carcinomas having aggressive clinical behaviour.

Background: Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets. Methods: In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib. Results: These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src. Conclusion: Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.

Background: Since signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in hepatocellular carcinoma (HCC) and plays a key role in this tumor progression. Inhibition of the STAT3 signaling pathway has been considered as an effective therapeutic strategy for suppressing HCC development. Objective: In this study, we investigated the anti-cancer effects of EH-42 on HCC cells and tried to explain the underlying mechanism. Methods: MTT assay, colon formation assay and AnnexinV-FITC/PI double-staining assay were performed to assess the effects of EH-42 on cell growth and survival. Wound healing assay and transwell invasion assay were performed to assess the effects of EH-42 on cell migration and invasion. Western blotting assay was performed to analyze the effects of EH-42 on relative proteins. Results: According to the MTT assay, colon formation assay and AnnexinV-FITC/PI doublestaining assay, EH-42 could suppress the growth and induce apoptosis of HCC cells in a dosedependent manner. Further western blotting assay showed that the inhibitory effects of EH-42 on cell growth and survival were caused by activating caspase 3/9, suppressing the phospho-STAT3 (Tyr 705) and downregulating anti-apoptotic proteins like Bcl-2/Bcl-xL. Moreover, migration and invasion abilities of HCC cells were also inhibited by EH-42 in the wound healing assay and transwell invasion assay. The potential mechanism was that EH-42 could inhibit HCC metastasis via reversing epithelial-mesenchymal transition and downregulating the secretion of MMPs. Conclusion: Taken together, these findings suggested that EH-42 could be a potential therapeutic agent for HCC treatment.