New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil.

The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is currently commercialized as erectile dysfunction treatment. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors and potent vasodilators, that extend the physiological effects of nitric oxide and cyclic guanosine monophosphate (cGMP) signaling. Although most of the biological implications of these signaling regulations remain unknown, they offer a large therapeutic potential for several diseases. In addition, some PDE5 inhibitors' molecular effects seem to play a key role in different illnesses such as kidney disease, diabetes mellitus, and cancer. In this review, we discuss the molecular effects of PDE5 inhibitors and their therapeutic repurposing in different types of cancer.

Hormone-Related Cancer and Autoimmune Diseases: A Complex Interplay to be Discovered.

Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.

SFRP1 increases TMPRSS2-ERG expression promoting neoplastic features in prostate cancer in vitro and in vivo.

BACKGROUND: Prostate cancer (PCa) is the second cause of cancer related death in North American men. Androgens play an important role in its progression by regulating the expression of several genes including fusion ones that results from structural chromosome rearrangements. TMPRSS2-ERG is a fusion gene commonly observed in over 50% of PCa tumors, and its expression can be transcriptionally regulated by the androgen receptor (AR) given its androgen responsive elements. TMPRSS2-ERG could be involved in epithelial-mesenchymal transition (EMT) during tumor development. ERG has been reported as a key transcriptional factor in the AR-ERG-WNT network where five SFRP proteins, structurally similar to WNT ligands and considered to be WNT pathway antagonists, can regulate signaling in the extracellular space  by binding to WNT proteins or Frizzled receptors. It has been shown that over-expression of SFRP1 protein can regulate the transcriptional activity of AR and inhibits the formation of colonies in LNCaP cells. However, the effect of SFRP1 has been controversial since differential effects have been observed depending on its concentration and tissue location. In this study, we explored the role of exogenous SFRP1 protein in cells expressing the TMPRSS2-ERG fusion. METHODS: To evaluate the effect of exogenous SFRP1 protein on PCa cells expressing TMPRSS2-ERG, we performed in silico analysis from TCGA cohort, expression assays by RT-qPCR and Western blot, cell viability and cell cycle measurements by cytometry, migration and invasion assays by xCELLigance system and murine xenografts. RESULTS: We demonstrated that SFRP1 protein increased ERG expression by promoting cellular migration in vitro and increasing tumor growth in vivo in PCa cells with the TMPRSS2-ERG fusion. CONCLUSIONS: These results suggest the possible role of exogenous SFRP1 protein as a modulator of AR-ERG-WNT signaling network in cells positive to TMPRSS2-ERG. Further, investigation is needed to determine if SFRP1 protein could be a target in against this type of PCa.

Anthocyanins of Blue Corn and Tortilla Arrest Cell Cycle and Induce Apoptosis on Breast and Prostate Cancer Cells.

Background: Breast and prostate cancer are frequently diagnosed neoplasias in women and men around the world. The signaling of the androgen receptor (AR) influences the development of both tumors. Since therapies focused to block the receptor's activity have not been fully effective, and have shown side effects, therapies based on natural compounds are promissory complementary alternatives in its treatment. Objective: The aim of this study was to determine the effect of anthocyanins from blue corn in cancer cell lines. Methods: We analyzed the antiproliferative effect of anthocyanins from raw and alkali-processed (tortillas) Mixteco blue corn in breast and prostate cancer cell lines MDA-MB-453 (subtype: triple negative) and LNCaP using methyltiazlyl-tetrazolium (MTT) and flow cytometry (FCM). The combination of anthocyanins and 2-amino-N-quinolin-8-yl-benzenesulfonamide (QBS) or nocodazole also were evaluated. The anthocyanins were isolated trough column chromatography (XAD-7).Results: Our results demonstrated that anthocyanin specially the ones obtained from tortillas, decreased cell viability and arrested cell cycle in G1 phase inducing apoptosis. Cytometry analysis shows an increased effect on apoptosis of MDA-MB-453 and LNCaP cells when tortilla anthocyanins and QBS were combined. Conclusions: This is the first report that suggest that anthocyanins from blue corn have an effect in cell cycle and viability so they could serve as adjuvants for breast and prostate cancer therapies and may prompt to deepen investigations to decipher its molecular properties. AbbreviationsARAndrogen ReceptorCIDIIRInterdisciplinary Center for Research on Integral Regional DevelopmentDHT5α-DihydrotestosteroneEREstrogen ReceptorPRProgesterone ReceptorQBSAmino-N-quinolin-8-yl-benzenesulfonamide.

Antioxidant and antiproliferative activity of blue corn and tortilla from native maize.

BACKGROUND: Blue corn is a cereal rich in phenolic compounds used to make blue tortillas. Tortillas are an important part of the Mexican diet. Blue corn and tortilla represent an important source of the natural antioxidants anthocyanins. However, studies on their biological activity on cancer cell lines are limited. The goal of this study was to evaluate the antioxidant and antiproliferative activity of blue corn and tortilla on different cancer cell lines. METHODS: Total polyphenol content, monomeric anthocyanins, and antioxidant activity by the DPPH and TBARS methods of blue corn and tortilla were determined. The anthocyanin profile of tortilla was obtained by means of HPLC-ESI-MS. The antiproliferative activity of blue corn and tortilla extract on HepG2, H-460, Hela, MCF-7 and PC-3 was evaluated by the MTT assay. RESULTS: Blue corn had higher content of total polyphenols and monomeric anthocyanins as well as lower percentage of polymeric color than tortilla; however, both showed similar antioxidant activity by DPPH. In addition, although a higher degradation of anthocyanins was observed on tortilla extract, both extracts inhibited lipid peroxidation (IC50) at a similar concentration. The anthocyanin profile showed 28 compounds which are primarily derived from cyanidin, including acylated anthocyanins and proanthocyanidins. Blue corn and tortilla extracts showed antiproliferative effects against HepG2, H-460, MCF-7 and PC-3 cells at 1000 µg/mL, however Hela cells were more sensitive at this concentration. CONCLUSION: This is the first report to demonstrate anticancer properties in vitro of tortilla derived from blue corn, suggesting that this product has beneficial health effects. In addition, blue corn could be a potential source of nutraceuticals with anticancer activity.