H9c2 Cardiomyocytes under Hypoxic Stress: Biological Effects Mediated by Sentinel Downstream Targets

The association between diabetes and cardiovascular diseases is well known. Related diabetes macro- and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. In this study, we analyzed the embryonic heart-derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. In addition, hypoxia induced a RhoA upregulation and a Bcl-2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Furthermore, a significant cell proliferation rate increases after the 1400W iNOS inhibitor administration was observed. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases

The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids

A major challenge in the clinical management of prostate cancer (PC) is to inhibit tumor growth and prevent metastatic spreading. In recent years, considerable efforts have been made to discover new compounds useful for PC therapy, and promising advances in this field were reached. Drugs currently used in PC therapy frequently induce resistance and PC progresses toward metastatic castration-resistant forms (mCRPC), making it virtually incurable. Curcumin, a commercially avail- able nutritional supplement, represents an attractive therapeutic agent for mCRPC patients. In the present study, we compared the effects of chemotherapeutic drugs such as docetaxel, paclitaxel, and cisplatin, to curcumin, on two PC cell lines displaying a different metastatic potential: DU145 (moder- ate metastatic potential) and PC-3 (high metastatic potential). Our results revealed a dose-dependent reduction of DU145 and PC-3 cell viability upon treatment with curcumin similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, we explored the EGFR-mediated signaling effects on ERK activation in DU145 and PC-3 cells. Our results showed that DU145 and PC-3 cells overexpress EGFR, and the treatment with chemotherapeutic agents or curcumin reduced EGFR expression levels and ERK activation. Finally, chemotherapeutic agents and curcumin reduced the size of DU145 and PC-3 spheroids and have the potential to induce apoptosis and also in Matrigel. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic efficacy for inhibiting PC growth, the results show the ability of curcumin used alone, or in combinatorial approaches, to impair the size and the viability of PC-derived spheroids

Apoptosis Induced by Piroxicam plus Cisplatin Combined Treatment Is Triggered by p21 in Mesothelioma

BACKGROUND: Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing. CONCLUSIONS/SIGNIFICANCE: Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21

Annurca Apple Biophenols’ Effects in Combination with Cisplatin on A549 Cells.

Background. The role of a healthy and balanced diet in cancer prevention should never be underestimated; some nutritional factors can reduce the side effects of chemotherapy or radiotherapy and contribute to increasing its effectiveness. Therefore, in recent years it has been thought to associate the administration of antioxidants to the chemotherapy approach that can protect non-tumor cells from the cytotoxic action of these drugs. However, the protective action of these substances could also limit the chemotherapy effects against the neoplastic cells themselves. Objective. In this context, the goal of this work was to test the viability of cultured human non-small lung cancer A549 cells in response to the combined administration of cisplatin (CDDP) and polyphenols. In particular, Annurca apple flesh polyphenol extract (AFPE) action was examined. Methods. A549 cells were treated with AFPE alone or in combination with CDDP and then cell viability was measured by the MTT assay. The effects of constituent polyphenols (+)-catechin, (–)-epicatechin, and caffeic acid) in AFPE were also evaluated. The cell morphology was observed by an inverted phase-contrast microscope. Results. CDDP reduced A549 cell viability in both concentration- and time-dependent manners. Polyphenols and CDDP coadministration did not interfere with the CDDP efficacy, in fact, the cellular vitality was found to be similar to that detected in the samples treated with CDDP alone. Conclusion. In conclusion, the co-administration of AFPE with CDDP does not interfere with its chemotherapy efficacy. Therefore, Annurca apple could be good candidates to act as antioxidant and potentially reduce the side effects of CDDP therapy, although the joint effect of AFPE and CDDP on normal cells is still unclear. More studies will be needed to analyze the molecular mechanism of AFPE and in vivo studies will also be needed to verify the anticancer effects. These findings may represent a starting point for the design of new clinical trials for use in cancer treatment