Induction of cancer cell apoptosis by α‐tocopheryl succinate: molecular pathways and structural requirements

Abstract

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

“…It is increasingly recognized that mitochondria are emerging as effective targets that may provide the selectivity needed for potent anti-cancer therapy (Neuzil et al, 2001b;Don and Hogg, 2004). Studies with mitocans have shown exciting potential for cancer therapy since these drugs have limited side effects, and some of these compounds possess specificity for cancer cells (Neuzil et al, 2007).…”

“…MitoQ overcame both the TTFAand a-TOS-mediated inhibition of SDH activity. While TTFA binds to both Q P and Q D sites in CII (Sun et al, 2005) like a-TOS, it displays less selective toxicity ) than the VE analogue for killing cancer cells (Neuzil et al, 2001b). Further studies are required to understand this differential specificity.…”

Vitamin E analogues as inducers of apoptosis: structure–function relation

“…In this regard, recent findings suggest that certain analogues of vitamin E (VE), such as a-tocopheryl succinate (a-TOS), may represent a new class of antineoplastic agents with high selectivity for malignant cells and low toxicity. a-Tocopheryl succinate causes apoptotic death of a variety of neoplastic cell lines (Fariss et al, 1994;Qian et al, 1997;Neuzil et al, 1999;Yamamoto et al, 2000), whereas neither the redox-active a-tocopherol (a-TOH) nor its uncharged ester, a-tocopheryl acetate (a-TOA), is effective (Qian et al, 1997;Neuzil et al, 2001c). Therefore, the proapoptotic activity appears to be a unique feature of a-TOS, and this agent is also effective in vivo, inhibiting the growth of colon (Weber et al, 2002) and melanoma cancers (Malafa et al, 2001), promoting breast cancer dormancy (Malafa and Neitzel, 2000), and suppressing metastasis (Barnett et al, 2002).…”

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

“…The apoptotic effect of a-TOS involves lysosomal and mitochondrial destabilisation as well as caspase-3 activation Neuzil et al, 2001b). a-Tocopheryl succinate-induced apoptosis may be amplified by protein kinase C (PKC) inhibition (Neuzil et al, 2001b).…”

“…The apoptotic effect of a-TOS involves lysosomal and mitochondrial destabilisation as well as caspase-3 activation Neuzil et al, 2001b). a-Tocopheryl succinate-induced apoptosis may be amplified by protein kinase C (PKC) inhibition (Neuzil et al, 2001b). Recently, a-TOS has been shown to exert antineoplastic activity and to promote tumour dormancy in preclinical models (Malafa and Neitzel, 2000;Weber et al, 2002).…”