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.
Highlights
Mitochondria have recently emerged as intriguing targets for anti-cancer drugs [1,2,3]
While a-tocopheryl succinate (a-TOS) alone induced a late formation of peroxide-related molecules, which was observed after 120 min of incubation, it reduced the early increase in their levels in response to the treatment of the cells with vitamin K3 (VK3) and ascorbic acid (AA) alone (Fig. 1A, left panel)
The DHE-derived ethidium bromide (EtBr) nuclear staining was detected over time using fluorescence microscopy, and indicates that upon treatment with VK3 and AA, the apoptotic blebs containing nuclear components were formed at the cell surface after 60–120 min; 36–46% of cells were EtBr-negative as a consequence of chromatin loss
Summary
Mitochondria have recently emerged as intriguing targets for anti-cancer drugs [1,2,3]. To potentiate its anti-cancer effect, VK3 has been combined with the redox-active ascorbic acid (AA). In response to oxidative stress cells activate pathways that promote their survival and adaptation [7]. One such stress-response mechanism is autophagy [8,9]. The redox-silent vitamin E analog a-tocopheryl succinate (a-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. We investigated the molecular mechanism(s) underlying cell death induced in prostate cancer cells by a-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer
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