Clinical Cancer Drugs - Volume 3, Issue 1, 2016

Background: Recently, a number of genetic aberrations have been associated to prostate cancer, these can either cause prostate cancer directly by affecting mechanisms central to the survival of the prostatic cell or indirectly by making the cell more sensitive to endocrine or paracrine stimuli. The mature IGF-1 is one of the most common factors involved in the development of prostate cancer. Its mode of action is exerted through the IGF-1R. It induces inhibition of apoptosis, thus promoting survival, and cellular proliferation. Methods: Review of the literature was carried out for the determination of all the molecules involved in prostate cancer pathophysiology. The papers were found using the Pubmed platform. Results: Evidence is presented for the involvement of a novel key player in prostate cancer, the Ec peptide of the IGF-1Ec isoform that is positively associated to stage and grade in prostate cancer patients and is associated with induction of cellular proliferation epithelial to mesenchymal transition and metastases of prostate cancer cells. Conclusion: Herein we review the current knowledge in the prostate cancer genetic landscape stressing out new evidence in the literature regarding the role of the Ec peptide (PEc) of the IGF-1Ec isoform in prostate cancer.

Background: Prostate cancer (PCa) patients shall develop eventually incurable bone metastasis. Although advanced prostate cancer is the best known example of androgen- dependent neoplasia, PCa patients after an excellent clinical response to adrogen ablation therapies (medical or surgical castration) will ultimately become castration resistant (CRPC). Methods: Analysis of cell-cell interactions within the sites of osteoblastic metastasis has revealed that survival factors (inhibitors of chemotherapy-induced apoptosis and androgen deprivation/medical or surgical castration-induced apopptosis) for prostate cancer cells are activated, locally. Results: The analysis of these cell-cell interactions between metastatic PCa cells and host tissue (bone) revealed that insulin-like growth factor I, transforming growth factor beta 1 (TGFβ1), interleukin 6 (IL-6) are the most important survival factors for prostate cancer cells residing in bones. Suppression of the bioavailability of such survival factors which can achieved by the administration of dexamethasone plus somatostatin analogues (anti-survival factor therapy: ASF therapy) was proven an effective hormonal manipulation for the treatment of CRPC. Conclusion: The present review provides an update on bone microenvironment cell-cell interactions forming the concept of the ASF therapy for CRPC.

Background: The importance of epigenetics in cancer is well known. Since many epigenetic mechanisms are involved in cancer progression, they may represent a target for a new pharmacological approach. Prostate cancer is the most common malignancy in men. After failure of the androgen deprivation therapy, the recurrent disease is termed castration- resistant cancer (CRPC). Since CRPC remains an incurable disease, new studies are focusing on the mechanisms critical for CRPC development, to identify new pharmacological targets. Methods: A MEDLINE research related to CRPC and epigenome has been carried out. Results: CRPC is probably due to several genetic and epigenetic mechanisms involved in AR activation, even in the presence of low androgen levels. Increasing evidence suggests that an aberrant DNA methylation may promote CRPC progression, augmenting genomic instability. Deregulated miRNAs are involved in initiation, progression, and metastatization of prostate cancers. MiRNAs may act like oncogenes (oncomirs) which can promote cancer progression, or tumor suppressors (anti-oncomirs) which inhibit CRPC progression. miRNA replacement therapy represents the most promising anticancer strategy, however only MRX34 (a doublestranded RNA mimic of the anti-oncomir, miR-34) has reached phase I clinical trial. Also, the deregulation of long non coding RNAs (lncRNAs) has been involved in CRPC development and lncRNAs may gain diagnostic/ therapeutic relevance. Recently research was focused on the chromatin reader proteins containing bromodomain and extraterminal domain (BET family). Since BET inhibitors act downstream of AR, these compounds might be effective in a condition of mediated AR resistance to androgen deprivation. Conclusions: The recent finding about CRPC epigenome might provide several emerging treatment strategies to counteract efficiently the tumor progression.

Background: The serine/threonine protein kinase, Akt, plays a key role in the modulation of cellular proliferation, tumour growth and survival through phosphorylation of different downstream molecules. Here we review the recent progress in studying roles of the phosphatydil-4-5-bisphosphate-3-kinase (PI3K)/Akt/mTOR pathway in prostate cancer (PCa) therapy, mainly focusing on the effects of inhibitors targeting this signalling pathway in the treatment of PCa to improve standard therapies in preclinical studies as well as the results of clinical trials in prostate cancers. Methods: A computerised search was performed to identify all relevant studies in Medline. Additional articles were extracted based on recommendations from an expert panel of authors. This review summarizes the development of the compounds able to inhibit single elements of PI3K/Akt/mTOR pathways and provides the mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic PCa. Results: The activation of Akt triggers the mammalian target of rapamycin (mTOR) signaling pathways as an essential mechanism to escape the controls on proliferation and apoptosis following therapy. Phosphatase and tensin homolog (PTEN) is the central negative regulator of this cascade and is genetically and functionally silenced in PCa with high frequency. AKT relieves the negative regulation of mTOR to activate protein synthesis and cell proliferation through S6K and 4EBP1. Conclusion: Accordingly, some PI3K, Akt and mTOR inhibitors have been tested as cancer therapeutic agents alone or in combination with standard therapies and showed sensitizing effects with radio-, hormoneand chemo-therapy.

Background: Celastrol is a bioactive compound extracted from the root bark of “Thunder God Vine” (Tripterygium wilfordii, Hook F.) with anticancer activities against a broad spectrum of human cancer models. This article is aimed to review the mechanisms of action of celastrol against different cancers, and to discuss the limitations restricting it from clinical trials as well as the potential resolutions. Methods: MEDLINE database up to January 2015 was searched using celastrol and cancer as queries. Results: Celastrol demonstrates efficacy against various cancers in the preclinical studies. It stabilizes the endogenous inhibitor of NF-ΚB by suppressing either upstream IKK activity or downstream proteasome degradation pathway. Celastrol inhibits Hsp90 chaperoning through disrupting Hsp90-Cdc37 interaction or inactivating co-chaperone protein p23. It also induces UPR in proteasome-dependent or -independent manners. In addition, Celastrol has been documented as a chemosensitizer to currently used chemotherapeutics. However, its poor water solubility and low bioavailability as well as severe side effects have limited its clinical application. Conclusion: Celastrol is an active natural product that exerts anti-cancer activity in a variety of cancers. It targets multiple molecules and pathways that are essential for tumor formation and development in preclinical setting. In spite of its remarkable pharmacological effects, celastrol is restricted from any clinical application due to severe adverse effects and poor bioavailability. Although drug delivery systems have improved the solubility and bioavailability, only very few drug delivery system-based cancer therapeutics have successfully entered clinical trials. Thus, it is important to address the challenges while developing optimized delivery systems for celastrol clinical use in the future.