Current Cancer Drug Targets - Volume 18, Issue 10, 2018

The B-cell lymphoma 2 (Bcl-2) family proteins play an important role in regulating apoptosis, or programmed cell death, in response to several extracellular and intracellular signals. These proteins are either pro-apoptotic or anti-apoptotic. The pro-apoptotic Noxa is a Bcl-2 family protein that belongs to a subclass of BH3-only proteins. Noxa induces apoptosis via p53-dependent and/or p53-independent mechanisms. While Noxa may play a limited role in apoptosis, it is a crucial player that interacts with several proteins in the apoptosis pathway, highlighting its importance in the pathogenesis and treatment of certain cancers. In this review, we will elucidate the mechanisms by which Noxa regulates apoptosis and review the roles of chemotherapeutic drugs in relation to Noxa.

Prostate cancer (PCa) is the most common non-skin cancer in men worldwide, resulting in significant mortality and morbidity. Depending on the grade and stage of the cancer, patients may be given radiation therapy, hormonal therapy, or chemotherapy. However, more than half of these patients develop resistance to treatment, leading to disease progression and metastases, often with lethal consequences. MicroRNAs (miRNAs) are short, non-coding RNAs, which regulate numerous physiological as well as pathological processes, including cancer. miRNAs mediate their regulatory effect predominately by binding to the 3′-untranslated region (UTR) of their target mRNAs. In this review, we will describe the mechanisms by which miRNAs mediate resistance to radiation and drug therapy (i.e. hormone therapy and chemotherapy) in PCa, including control of apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition (EMT), invasion and metastasis, and cancer stem cells (CSCs). Furthermore, we will discuss the utility of circulating miRNAs isolated from different body fluids of prostate cancer patients as non-invasive biomarkers of cancer detection, disease progression, and therapy response. Finally, we will shortlist the candidate miRNAs, which may have a role in drug and radioresistance, that could potentially be used as predictive biomarkers of treatment response.

PRDM14 belongs to the PR domain-containing (PRDM) family. Although a precise understanding focused on the function of PRDM14 to maintain stemness and pluripotency in embryonic stem cells via epigenetic mechanisms, growing experimental evidence has been linked PRDM14 to human cancers. In adults, PRDM14 has low expression in human tissues. Aberrant PRDM14 expression is connected with various malignant histological types and solid cancers, where PRDM14 can act as a driver of oncogenic processes. Overexpression of RPDM14 enhanced cancer cells growth and reduced cancer cells sensitive to chemotherapeutic agents. Reducing the expression of PRDM14 in cancer cells can enhance the therapeutic sensitivity of drugs to cancer cells, suggesting that aberrant PRDM14 may have a carcinogenic characteristic in tumor therapy and as a new molecular target. This review summarizes the structure and oncogenic properties of PRDM14 in different malignancies and suggests that PRDM14 may be a potential therapeutic molecular target for tumor treatment.

Background: Essential oils are complex mixtures of low molecular weight compounds extracted from plants. Their main constituents are terpenes and phenylpropanoids, which are responsible for their biological and pharmaceutical properties, such as insecticidal, parasiticidal, antimicrobial, antioxidant, anti-inflammatory, analgesic, antinociceptive, anticarcinogenic, and antitumor properties. Cancer is a complex genetic disease considered as a serious public health problem worldwide, accounting for more than 8 million deaths annually. Objective: The activities of prevention and treatment of different types of cancer and the medicinal potential of essential oils are addressed in this review. Conclusion: Several studies have demonstrated anti-carcinogenic and antitumor activity for many essential oils obtained from various plant species. They may be used as a substitution to or in addition to conventional anti-cancer therapy. Although many studies report possible mechanisms of action for essential oils compounds, more studies are necessary in order to apply them safely and appropriately in cancer therapy.

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors' biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

Background: Endocrine resistance and metastatic dissemination comprise major clinical challenges for breast cancer treatment. The fibroblast growth factor receptor family (FGFR) consists of four tyrosine kinase transmembrane receptors, involved in key biological processes. Genomic alterations in FGFR have been identified in advanced breast cancer and thus, FGFR are an attractive therapeutic target. However, the efficacy of FGFR inhibitors on in vivo tumor growth is still controversial. Objective: The purpose of this study was to evaluate the role of FGFR in tumor growth and breast cancer progression. Methods: Cell proliferation was assessed by 3H-thymidine uptake and cell counting in primary cultures of endocrine resistant mammary carcinomas and a human cell line, respectively. Tumor transplants and cell injections were used to determine in vivo growth and spontaneous metastasis. FGFR1-3 and αSMA expression were evaluated on primary tumors by immunohistochemistry. Results: Antiprogestin resistant murine transplants and a human xenograft express high levels of total FGFR1-3. In vitro treatment with the FGFR inhibitor, BGJ398, impaired cell proliferation of resistant variants versus vehicle. In vivo, versus control, BGJ398 treatment decreased one out of four resistant tumors, however all tumors showed a decreased epithelial/stromal ratio. Finally, in a model of hormone resistant mammary cancer that spontaneously metastasizes to the lung, BGJ398 decreased the number of mice with lung metastasis. Conclusion: FGFR inhibitors are promising tools that require further investigation to identify sensitive tumors. These studies suggest that targeting FGFR combined with other targeted therapies will be useful to impair breast cancer progression.

Background: Uveal melanoma is the most common primary intraocular malignancy in adults. So far, there have been no effective targeted therapeutic agents in patients with uveal melanoma. Artesunate is a semi-synthetic derivative of artemisinin extracted from traditional Chinese medicine Artemisia annua L for treatment of severe and multidrug-resistant malaria. Besides its antimalarial activity, artesunate is identified as an anti-cancer drug due to the inhibition of Wnt/β- catenin pathway in multiple types of cancer. However, the effect of artesunate on uveal melanoma remains unknown. Objective: We evaluated the anti-tumor effects of artesunate on uveal melanoma cells, and analyzed in terms of Wnt/β-catenin pathway, cell growth, cell death, cell migration, invasion and cancer stemlike cells (CSCs) properties. Methods: Primary (92.1, Mel270) and metastatic (Omm1 and Omm2.3) uveal melanoma cells were used. Immunofluorescence staining, dual luciferase reporter assay, Western blotting, MTS, soft agar cloning technique, Annexin V/PI analyses, wound healing scratch assay, in vitro transwell migration and invasion assays, aldehyde dehydrogenase (ALDH) analyses and melanosphere formation assay et al. were carried out. Results: Artesunate suppressed the phosphorylation of GSK3β at S9, and lowered the protein level of β-catenin and its downstream targets (c-Myc, cyclin D1). Artesunate potently inhibited cell viability and colony formation ability. Treatment with artesunate significantly induced apoptosis. In addition, artesunate significantly reduced the migration and invasion of uveal melanoma cells, impaired the traits of CSCs in vitro. Conclusion: Artesunate may be a potential interest for the therapy of uveal melanoma.