Targeting mitochondria by α-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment
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Rapidly proliferating tumor cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs. Here, we show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin. The stimulation of apoptosis, as assessed by the number of cells in the SubG1 fraction of the cell cycle, release of cytochrome c into the cytosol, activation of caspase-3, and cleavage of PARP, was markedly suppressed under low oxygen content or when hypoxia was mimicked by deferoxamine. Hypoxia or deferoxamine treatment was accompanied by stabilization of the hypoxia-inducible factor (HIF-1). The downregulation of HIF-1 using siRNA technique restored cell sensitivity to treatment under hypoxic conditions to the levels detected under normoxic conditions. In contrast to cisplatin or doxorubicin, α-tocopheryl succinate (α-TOS), a compound that targets mitochondria, stimulated cell death irrespective of the oxygen concentration. Moreover, under hypoxic condition cell death induced by α-TOS was even enhanced. Thus, α-TOS can successfully overcome resistance to treatment caused by hypoxia, which makes α-TOS an attractive candidate for antitumor therapy via mitochondrial targeting.
KeywordsMitochondria Apoptosis Hypoxia Tumor α-tocopheryl succinate
The authors are indebted to Prof. Maria Alfonsina Desiderio (University of Milan) for providing the reporter construct of the hypoxia response element and Björn Kruspig (Karolinska Institutet) for technical assistance. The work was supported by Megagrant from the Russian Ministry of High Education and Science, grants from the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Swedish and the Stockholm Cancer Societies, the EC FP-6 (Chemores), and the EC FP7 (Apo-Sys) programs, and the Russian Foundation for Basic Research. AVK has been awarded a grant of the President of the Russian Federation for the young scientists.
- 7.Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292(5516):468–472. doi: 10.1126/science.1059796 PubMedCrossRefGoogle Scholar
- 12.Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM (1995) Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81(5):801–809 pii: 0092-8674(95)90541-3PubMedCrossRefGoogle Scholar
- 23.Dong LF, Low P, Dyason JC, Wang XF, Prochazka L, Witting PK, Freeman R, Swettenham E, Valis K, Liu J, Zobalova R, Turanek J, Spitz DR, Domann FE, Scheffler IE, Ralph SJ, Neuzil J (2008) Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 27(31):4324–4335. doi: 10.1038/onc.2008.69 PubMedCentralPubMedCrossRefGoogle Scholar
- 24.D’Alessio M, De Nicola M, Coppola S, Gualandi G, Pugliese L, Cerella C, Cristofanon S, Civitareale P, Ciriolo MR, Bergamaschi A, Magrini A, Ghibelli L (2005) Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. FASEB J 19(11):1504–1506. doi: 10.1096/fj.04-3329fje PubMedGoogle Scholar