Research: KULIKOW and COLLEAGUES,

Listed in Issue 240

Abstract

KULIKOW and COLLEAGUES, (1) Faculty of Basic Medicine, MV Lomonosov Moscow State University, 119991, Moscow,  Russia showed that α-tocopheryl succinate (α-TOS) can overcome resistance to cancer treatment caused by hypoxia.

Background

Rapidly proliferating tumour cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs.

Methodology

Here, the authors show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin.

Results

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.

Conclusion

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.

References

Kulikov AV(1), Vdovin AS, Zhivotovsky B, Gogvadze V. Targeting mitochondria by α-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment. Cell Mol Life Sci. 71(12):2325-33. Jun 2014. doi: 10.1007/s00018-013-1489-8. Epub  Oct 19 2013.

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