Prolonged exposure of resveratrol induces reactive superoxide species–independent apoptosis in murine prostate cells

Abstract

Nitric oxide, a signaling molecule, inhibits mitochondrial respiration by binding with cytochrome c oxidase, resulting in elevated production of reactive superoxide species (reactive oxygen and nitrogen) in the mitochondria and increased susceptibility to cell death. Generation of mitochondrial superoxide species can be suppressed by natural compounds such as resveratrol, a dietary polyphenol found in the skin of red fruits. In various cancer cells, resveratrol shows anti-oxidant and cancer preventive properties. Since, the effect of resveratrol on reactive superoxide species-independent apoptosis in prostate cancer cells is not well illustrated; therefore, we investigated this phenomenon in TRAMP murine prostate cancer cells. To accomplish this, TRAMP cells were incubated with resveratrol, resveratrol + DETA-NONOate, DETA-NONOate (nitric oxide donor), resveratrol + L-NMMA, or L-NMMA (nitric oxide inhibitor) for 48 h, and reactive superoxide species in the mitochondria and culture supernatant were measured. In addition, the mitochondrial membrane potential, cell viability, expression of apoptotic markers (Bax and Bcl2), γ-H2A.x, p53, and caspase-3 was determined. We found that resveratrol suppressed reactive superoxide species such as reactive oxygen species in the mitochondria and nitric oxide in culture supernatant when compared to the DETA-NONOate treatment and disrupted the mitochondrial membrane potential. Resveratrol also reduced cell viability, altered the expression of apoptotic markers (Bax and Bcl2), and increased expression of γ-H2A.x (indicative marker of DNA fragmentation) and p53 (a critical DNA damage response protein). However, there was no appreciable modulation of the caspase-3. Therefore, our data suggest that resveratrol induces superoxide species-independent apoptosis and may act as a therapeutic agent against prostate cancer.

Direct and Indirect Inhibition Effects of Resveratrol against Toxoplasma gondii Tachyzoites In Vitro

“…Cell death of tachyzoites. Since resveratrol has been considered to alter the signaling pathway for apoptosis in many tumor cells (24,25) and we already saw its potential for RH tachyzoite inhibition, we were interested in examining whether it could promote phosphatidylserine (PS) exposure as a marker of the initiation of the early apoptotic process. We stimulated RH tachyzoites with resveratrol (50 M) for 12 h, followed by PS detection through annexin V-fluorescein isothiocyanate (FITC) labeling.…”

Polyphenols and Metabolites Enhance Survival in Rodents and Nematodes—Impact of Mitochondria

“…Concerning the effects of polyphenols on ΔΨm, growing evidence suggests a beneficial effect, but the literature is somewhat inconsistent. While Qi et al report an improved membrane potential after treatment with tea polyphenols in SH-SY5Y cells [85] or an increased potential through resveratrol in rats with diabetic cardiomyopathy [86], Kumar et al found a disrupted ΔΨm after prolonged exposure to resveratrol in murine prostate cancer cells [87].…”

Natural Compounds in Prostate Cancer Prevention and Treatment: Mechanisms of Action and Molecular Targets

“…This article provides an overview of recent findings about the anti-PCa activity of different natural compounds (Figure 2, Table 1). [47][48][49][50][51][52][53][54]80,100,107,123,124,[135][136][137][138][139]161,163,164,186,190,191,212] The use of phytochemicals for PCa management offers several advantages. Firstly, natural products are safe and well tolerated, as well as usually economically affordable.…”

“…Indeed, while apigenin, luteolin, genistein, and celastrol inhibited the proteasomal activity and caused ubiquitinated protein accumulation in different PCa cell lines [154][155][156], quercetin, curcumin, silibinin, and tannic acid induced endoplasmic reticulum (ER) stress [157][158][159][160], a condition where unfolded/misfolded proteins accumulate in the ER lumen and promote the activation of distinct pro-death cascades, including the double-stranded RNA-dependent protein kinase PKR-like ER kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) pathway and the inositol-requiring enzyme 1α (IRE1)/c-Jun N-terminal kinase (JNK)/p38 MAPK cascade [161]. Notably, curcumin-and silibinin-mediated ER stress was associated with generation of reactive oxygen species (ROS) and redox homeostasis alteration [159,162], which were also observed in resveratrol-and sulforaphane-treated PCa cells [163][164][165][166].…”