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

0392315 - ÚOCHB 2014 RIV US eng J - Journal Article
Procházka, L. - Koudelka, Š. - Dong, L. F. - Štursa, Jan - Goodwin, J. - Neca, J. - Slavík, J. - Cigánek, M. - Mašek, J. - Klučková, Katarína - Nguyen, M. - Turánek, J. - Neužil, Jiří
Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to alpha-tocopheryl succinate.
Apoptosis. Roč. 18, č. 3 (2013), s. 286-299. ISSN 1360-8185. E-ISSN 1573-675X
R&D Projects: GA ČR GAP301/10/1937; GA ČR(CZ) GAP304/10/1951
Grant - others:GA ČR(CZ) GP204/09/P632
Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z40550506
Keywords : vitamin E analogues * apoptosis * mitochondrial targeting * ABCA1 * acquired resistance
Subject RIV: CE - Biochemistry; EA - Cell Biology (BTO-N)
Impact factor: 3.614, year: 2013

alpha-Tocopheryl succinate (alpha-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 alpha-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 alpha-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 alpha-TOS. The resistance of the cells to alpha-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 alpha-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.
Permanent Link: http://hdl.handle.net/11104/0221219