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

Lubomir Prochazka1, Stepan Koudelka, Lan-Feng Dong

  • 1Veterinary Research Institute, Brno, Czech Republic. lubomir.pr@gmail.com

Apoptosis : an International Journal on Programmed Cell Death
|January 10, 2013
PubMed

Insights

Long-term exposure to alpha-tocopheryl succinate (α-TOS) can cause cancer cell resistance by upregulating ABCA1 protein. A mitochondrially targeted analogue, MitoVES, overcomes this resistance, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Alpha-tocopheryl succinate (α-TOS) shows promise as a selective anti-cancer agent.
  • Understanding potential drug resistance mechanisms is crucial for therapeutic efficacy.

Purpose of the Study:

  • To investigate the development of resistance in cancer cells upon long-term exposure to α-TOS.
  • To explore strategies for overcoming α-TOS resistance.

Main Methods:

  • Exposure of non-small cell lung carcinoma H1299 and A549 cells to escalating doses of α-TOS.
  • ABCA1 protein and gene expression analysis.
  • ABCA1 protein knockdown experiments.
  • Treatment with mitochondrially targeted α-TOS analogue (MitoVES).
  • In vivo studies using mouse tumor models.

Main Results:

  • Long-term α-TOS exposure led to resistance in H1299 and A549 cells, associated with ABCA1 protein upregulation and increased efflux.
  • Knocking down ABCA1 restored sensitivity to α-TOS.
  • MitoVES effectively overcame α-TOS resistance by bypassing ABCA1-mediated efflux.
  • In vitro findings were validated in mouse models.

Conclusions:

  • Acquired resistance to α-TOS in cancer cells is mediated by ABCA1 upregulation.
  • Mitochondrially targeted analogues like MitoVES can circumvent ABCA1-mediated resistance.
  • These findings have implications for clinical trial design involving vitamin E analogues.

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