Current Cancer Drug Targets - Volume 19, Issue 5, 2019

The use of photodynamic therapy in cancer still remains limited, partly because of the lack of photosensitizer (PS) specificity for the cancerous tissues. Various molecular tools are available to increase PS efficiency by targeting the cancer cell molecular alterations. Most strategies use the protein-protein interactions, e.g. monoclonal antibodies directed toward tumor antigens, such as HER2 or EGFR. An alternative could be the targeting of the tumor glycosylation aberrations, e.g. T/Tn antigens that are truncated O-glycans over-expressed in numerous tumors. Thus, to achieve an effective targeting, PS can be conjugated to molecules that specifically recognize the Oglycosylation aberrations at the cancer cell surface.

Polyploidy is associated with increased cell size and is commonly found in a subset of adult organs and blastomere stage of the human embryo. The polyploidy is formed through endoreplication or cell fusion to support the specific need of development including earliest embryogenesis. Recent data demonstrated that Polyploid Giant Cancer Cells (PGCCs) may have acquired an activated early embryonic-like program in response to oncogenic and therapeutic stress to generate reprogrammed cancer cells for drug resistance and metastasis. Targeting PGCCs may open up new opportunities for cancer therapy.

Prostate cancer (PCa) is the most frequent cancer in men. The evolution from local PCa to castration-resistant PCa, an end-stage of disease, is often associated with changes in genes such as p53, androgen receptor, PTEN, and ETS gene fusion products. Evidence is accumulating that repurposing of metformin (MET) and valproic acid (VPA) either when used alone, or in combination, with another therapy, could potentially play a role in slowing down PCa progression. This review provides an overview of the application of MET and VPA, both alone and in combination with other drugs for PCa treatment, correlates the responses to these drugs with common molecular changes in PCa, and then describes the potential for combined MET and VPA as a systemic therapy for prostate cancer, based on potential interacting mechanisms.

The stability of mRNA is one of the key factors governing the regulation of eukaryotic gene expression and function. Human antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. While HuR is normally localized within the nucleus, it has been shown that HuR binds mRNAs in the nucleus and then escorts the mRNAs to the cytoplasm where HuR protects them from degradation. It contains several RNA recognition motifs, which specifically bind to adenylate and uridylate-rich regions within the 3’-untranslated region of the target mRNA to mediate its effect. Many of the HuR target mRNAs encode proteins important for cell growth, tumorigenesis, angiogenesis, tumor inflammation, invasion and metastasis. HuR overexpression is known to correlate well with high-grade malignancy and poor prognosis in many tumor types. Thus, HuR has emerged as an attractive drug target for cancer therapy. Novel small molecule HuR inhibitors have been identified by high throughput screening and new formulations for targeted delivery of HuR siRNA to tumor cells have been developed with promising anticancer activity. This review summarizes the significant role of HuR in cancer development, progression, and poor treatment response. We will discuss the potential and challenges of targeting HuR therapeutically.

Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric malignancies. Although it has shown promise as a biotherapeutic, its cardiotoxicity remains a major concern. Genotoxic anticancer anthracyclines such as doxorubicin and epirubicin are also known for their cardiotoxic effects. However, trastuzumab and anthracyclines are suggested to mediate cardiotoxicity via different pathways. The available lines of evidence suggest that trastuzumab can exacerbate the cardiotoxic effects of anthracyclines and thus, prior exposure to anthracyclines is regarded as one of the risk factors for trastuzumab-induced cardiotoxcity. Although it is generally believed that the trastuzumab-induced cardiotoxic effects are reversible, various preclinical studies have revealed its apoptotic effects on cardiomyocytes. Thus, the issue of the reversibility of its cardiotoxic effects remains to be fully resolved. This article discusses various mechanisms that have been proposed for the cardiotoxic effects of trastuzumab and the potential risk factors that can lead to cardiotoxicity. The recently approved anti-HER2 monoclonal antibodies including pertuzumab and ado-trastuzumab (T-DM1) are also discussed.

Background: Cancer remains one of the most serious disease worldwide. Robust metabolism is the hallmark of cancer. PPAT (phosphoribosyl pyrophosphate amidotransferase) catalyzes the first committed step of de novo purine biosynthesis. Hence PPAT, the key regulatory spot in De novo purine nucleotide biosynthesis, is an attractive and credible drug target for leukemia and other cancer therapeutics. Objective: In the present study, detailed computational analysis has been performed for PPAT protein, the key enzyme in de novo purine biosynthesis which is inhibited by many folate derivatives, hence we aimed to investigate and gauge the inhibitory effect of antifolate derivatives; lomexterol (LTX) methotrexate (LTX), and pipretixin (PTX) with human PPAT to effectively capture and inhibit De novo purine biosynthesis pathway. Methods: The sequence to structure computational approaches followed by molecular docking experiments was performed to gain insight into the inhibitory mode, binding orientation and binding affinities of selected antifolate derivatives against important structural features of PPAT. Results: Results indicated a strong affinity of antifolate inhibitors for the conserved active site of PPAT molecule encompassing a number of hydrophobic, hydrogen bonding, Vander Waals and electrostatic interactions. Conclusion: Conclusively, the strong physical interaction of selected antifolate inhibitors with human PPAT suggests the selective inhibition of De novo purine biosynthesis pathway by antifolate derivatives towards cancer therapeutics.

Background: Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunction of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. Objective: We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer. Methods: The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. siRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay. Results: We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene impeded IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability in pancreatic cancer cells. Conclusion: Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors