Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death

Abstract

BackgroundThe redox-silent vitamin E analog α-tocopheryl succinate (α-TOS) was found to synergistically cooperate with vitamin K3 (VK3) plus ascorbic acid (AA) in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s) underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer.Methodology/Principal FindingsThe generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF) release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects.Conclusions/Significanceα-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

“…Plasma concentration after a certain dose of applied redox-modulating agents taken is difficult to control. As a result, low concentrations may antagonise cytotoxic effects of anti-neoplastic drugs in cancer [189] cells, thus detrimentally affecting the therapeutic response. Therefore, additional efforts are needed for clinical development of the most promising redox-modulating agents that would give hope for improved tumour therapy.…”

“…Treatment with -TOS/VK3/AA significantly inhibited tumour growth (days 43-49, p = 0.04), inducing wide areas of cell death associated with AIF nuclear translocation, as compared to the control animals and those treated with the individual drugs. Notably, the anti-tumour effect of the -TOS and VK3/AA combination was associated with no signs of secondary deleterious effects [189].…”

“…In response to this oxidative stress, the cells activated the survival autophagic pathway. Inclusion of -TOS (redoxsilent agent) in the combinatorial treatment of cells inhibited the adaptive mechanisms and survival, leading to induction of cell death in prostate cancer [189]. It was observed that -TOS, at a sub-apoptotic dose, lowered ROS levels induced by the redox-active system.…”

The crucial role of vitamin C and its transporter (SVCT2) in bone marrow stromal cell autophagy and apoptosis

“…We speculate that knockdown or down-regulation of SVCT2 transporter disturb cells anti-oxidant properties because of less availability of vitamin C which leads to weaker cell survival mechanism. Vitamin C is known for its antioxidant dependent autophagy and cell survival role in various cell types (Bridges et al 1987; Martin et al 2002; Gruss-Fischer et al 2002; Tannetta et al 2008; Hung et al 2010; Singletary et al 2008; Tomasetti et al 2012). Ours is the first study to demonstrate the critical role of SVCT2 transporter in antioxidant effect of vitamin C on autophagy and cell survival in BMSCs.…”

New activity for old drug: In vitro activities of vitamin K3 and menadione sodium bisulfite against methicillin-resistant Staphylococcus aureus

“…The results showed that the anti-MRSA activity of compound 4 was basically equal to that of compound 5 by comparing their molar concentrations calculated from their MICs, while it was about twofold stronger than that of compound 1. Many new bioactivities of vitamin K 3 (compound 4 or 5) and its derivatives were discovered recently, such as anti-cancer (Matzno et al, 2008;Tomasetti et al, 2012;Tanahashi et al, 2011), anti-Alzheimer's disease (Huy, et al, 2013), anti-allergic and anti-inflammatory effects (Kohli et al, 2011;Chinzei et al, 2011). Here, the obvious antibacterial activity especially anti-MRSA activity of vitamin K 3 (compound 4 or 5) was first discovered by us, which showed that vitamin K 3 probably have an ancillary effect on the treatment of MRSA infection except for being used as vitamin K supplement and potential cancer treatment.…”