Caspase Mediated Enhanced Apoptotic Action of Cyclophosphamide- and Resveratrol-Treated MCF-7 Cells

Abstract

Abstract. Cyclophosphamide (CPA) is a widely used chemotherapeutic drug for neoplasias. It is a DNA and protein alkylating agent having a broad spectrum of activity against a variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the highdose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining resveratrol (RES) with CPA and aims to increase the understanding of the mechanism of cell killing. Interestingly, we found that RES significantly enhances the caspase-mediated cytotoxic activity of CPA on MCF-7 cells in vitro. RES at 50 μM decreases the IC 50 value of CPA from 10 to 5 mM. FACS data reveals CPA or RES alone mediated G0/ G1 and S phase arrest, while the combination of these drugs released both the arrests and results in an increase in the sub G0/G1 peak. Additional analyses indicated the significant up-regulation (P = 0.001) of tumor suppressor p53 and p53-regulated pro-apoptotic Bax and Fas in MCF-7 cells following CPA treatment in combination with RES, which may contribute to the enhancement of the antitumor effect of CPA. Furthermore, downregulation of anti-apoptotic Bcl-2 (P = 0.001) was observed in MCF-7 cells treated with CPA with or without RES when compared to untreated MCF-7. These results suggest the possibility of a new combination chemotherapeutic regimen leading to improvements in the treatment of breast cancer.

Resveratrol induces mitochondria-mediated, caspase-independent apoptosis in murine prostate cancer cells

“…Nevertheless, in U937 cells, overexpression of Bcl2 attenuates RES-mediated apoptosis by blocking caspase-3 activation [53]. Moreover, RES induces caspase-dependent and -independent apoptosis in various cancer cells [85–87]. In colon cancer cells, RES induces caspase-2 activation that subsequently triggers Bax-Bak-dependent and -independent cell death [79].…”

Role of polyphenols in cell death control

“…Indeed, the modulation of cell fate by polyphenols may be mediated through any of the numerous molecular mechanisms and signalling pathways that regulate (1) the activation of mitochondria and death caspases, (2) the up-regulation of cyclin-dependent kinase inhibitors, tumour suppressor gene products, or death-inducing cytokines and cytokine receptors, and (3) the downregulation of cell survival proteins or inhibition of cell survival kinases and survival transcription factors. [91][92][93][94][95][96][97][98] In this regard, an interesting paper by Kartal et al demonstrates in a cell model of myeloid leukaemia that the pro-apoptotic activity of resveratrol is mediated by increased generation and accumulation of apoptotic ceramides, bioactive sphingolipids that regulate many signalling pathways. 99 Kaempferol induces apoptosis by inactivating Akt, which is one of the most effective anti-apoptotic survival pathways in mammals, and by decreasing the expression of Bcl-2 and increasing the expressions of Bax, eventually inducing the intrinsic pathway in myelogenous leukaemia cell line K562 and promyelocitic human leukaemia U937 cells.…”

Resveratrol inhibits adventitial fibroblast proliferation and induces cell apoptosis through the SIRT1 pathway

“…The interaction or balance among these pathways finally decides the fate of cells. It has been shown that the activation of SIRT1 in different cells may act in two ways; one is to protect cells from the apoptosis induced by various conditions through regulating the expression and activity of the FOXO family; the other is to induce the activation of the caspase family and promote cell apoptosis (21,22). It has been shown that SIRT1 inhibits angiotensin II-induced vascular smooth muscle cell hypertrophy through modulating nicotinamide adenine dinucleotide phosphate oxidase 1 and GATA binding protein 6 (23).…”