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Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to α-tocopheryl succinate

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Abstract

α-Tocopheryl succinate (α-TOS) is a promising anti-cancer agent due to its selectivity for cancer cells. It is important to understand whether long-term exposure of tumour cells to the agent will render them resistant to the treatment. Exposure of the non-small cell lung carcinoma H1299 cells to escalating doses of α-TOS made them resistant to the agent due to the upregulation of the ABCA1 protein, which caused its efflux. Full susceptibility of the cells to α-TOS was restored by knocking down the ABCA1 protein. Similar resistance including ABCA1 gene upregulation was observed in the A549 lung cancer cells exposed to α-TOS. The resistance of the cells to α-TOS was overcome by its mitochondrially targeted analogue, MitoVES, that is taken up on the basis of the membrane potential, bypassing the enhanced expression of the ABCA1 protein. The in vitro results were replicated in mouse models of tumours derived from parental and resistant H1299 cells. We conclude that long-term exposure of cancer cells to α-TOS causes their resistance to the drug, which can be overcome by its mitochondrially targeted counterpart. This finding should be taken into consideration when planning clinical trials with vitamin E analogues.

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Acknowledgments

The authors wish to thank Dr. Vojtesek for providing the H1299 cells and Prof. Akporiaye for α-TEA. This study was supported in part by Grants from the Australian Research Council, the National Health and Medical Research Council of Australia, the Clem Jones Foundation and the Czech Science Foundation (P301/10/1937) to J.N, and by the Grant from the Czech Science Foundation 204/09/P632 to L.P and by the Grant CZ.1.07/2.3.00/20.0164 and P304/10/1951 (Czech Scientific Foundation) to J.T.

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Authors and Affiliations

  1. Veterinary Research Institute, Brno, Czech Republic

    Lubomir Prochazka, Stepan Koudelka, Jiri Neca, Josef Slavik, Miroslav Ciganek, Josef Masek & Jaroslav Turanek

  2. School of Medical Science, Griffith University, Southport, QLD, 4222, Australia

    Lan-Feng Dong, Jan Stursa, Jacob Goodwin, Maria Nguyen & Jiri Neuzil

  3. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Jan Stursa

  4. Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Katarina Kluckova & Jiri Neuzil

  5. Apoptosis Research Group, School of Medical Science and Griffith Health Institute, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia

    Lubomir Prochazka & Jiri Neuzil

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  1. Lubomir Prochazka
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  2. Stepan Koudelka
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Correspondence to Lubomir Prochazka or Jiri Neuzil.

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Prochazka, L., Koudelka, S., Dong, LF. et al. Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to α-tocopheryl succinate. Apoptosis 18, 286–299 (2013). https://doi.org/10.1007/s10495-012-0795-1

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