Targeting Mitochondrial Oxidative Phosphorylation Abrogated Irinotecan Resistance in NSCLC

Anticancer drug resistance is a major challenge of cancer therapy. We found that irinotecan-resistant NSCLC cells showed increased mitochondrial oxidative phosphorylation compared to the drug sensitive NSCLC cells. Previously, we found that combined inhibition of aldehyde dehydrogenase using gossypo...

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Published inScientific reports Vol. 8; no. 1; pp. 15707 - 11
Main Authors Lee, Soohyun, Lee, Jae-Seon, Seo, Jinho, Lee, Seon-Hyeong, Kang, Joon Hee, Song, Jaewhan, Kim, Soo-Youl
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 24.10.2018
Nature Publishing Group UK
Subjects
Aldehyde dehydrogenase
Cancer
Drug resistance
Electron transport chain
Gossypol
Irinotecan
Kinases
Lung cancer
Mitochondria
NADH-ubiquinone oxidoreductase
Non-small cell lung carcinoma
Oxidative phosphorylation
Phosphorylation
Xenografts
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Summary:Anticancer drug resistance is a major challenge of cancer therapy. We found that irinotecan-resistant NSCLC cells showed increased mitochondrial oxidative phosphorylation compared to the drug sensitive NSCLC cells. Previously, we found that combined inhibition of aldehyde dehydrogenase using gossypol, and mitochondrial complex I using phenformin, effectively reduced oxidative phosphorylation in NSCLC. Here, we showed that targeting oxidative phosphorylation with gossypol and phenformin abrogated irinotecan resistance in NSCLC. Furthermore, irinotecan treatment by blocking oxidative phosphorylation induced synergistic anti-cancer effect in NSCLC. The pre-clinical xenograft model of human NSCLC also demonstrated a therapeutic response to the dual targeting treatment. Therefore, this combination of gossypol and phenformin increases irinotecan sensitivity as well as preventing irinotecan resistance.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-33667-6