Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to α-tocopheryl succinate
Jazyk angličtina Země Nizozemsko Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- ABC transportéry genetika fyziologie MeSH
- ABCA1 protein MeSH
- alfa-tokoferol terapeutické užití MeSH
- antitumorózní látky farmakologie MeSH
- chemorezistence * MeSH
- genový knockdown MeSH
- mitochondrie účinky léků MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory plic farmakoterapie MeSH
- nemalobuněčný karcinom plic farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ABC transportéry MeSH
- ABCA1 protein MeSH
- alfa-tokoferol MeSH
- antitumorózní látky MeSH
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.
Citace poskytuje Crossref.org
Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy