The Involvement of Mitochondrial Membrane Potential in Cross-Resistance Between Radiation and Docetaxel

Yoshikazu Kuwahara, Mehryar Habibi Roudkenar, Masatoshi Suzuki, Yusuke Urushihara, Motoi Fukumoto, Yohei Saito, Manabu Fukumoto

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Purpose To understand the molecular mechanisms underlying cancer cell radioresistance, clinically relevant radioresistant (CRR) cells that continue to proliferate during exposure to 2 Gy/day X-rays for more than 30 days were established. A modified high-density survival assay for anticancer drug screening revealed that CRR cells were resistant to an antimicrotubule agent, docetaxel (DTX). The involvement of reactive oxygen species (ROS) from mitochondria (mtROS) in the cross-resistance to X-rays and DTX was studied. Methods and Materials Sensitivity to anticancer agents was determined by a modified high-density cell survival or water-soluble tetrazolium salt assay. DTX-induced mtROS generation was determined by MitoSOX red staining. JC-1 staining was used to visualize mitochondrial membrane potential. DTX-induced DNA double-strand breaks were determined by γ-H2AX staining. To obtain mitochondrial DNA-lacking (ρ0) cells, the cells were cultured for 3 to 4 weeks in medium containing ethidium bromide. Results Treatment with DTX increased mtROS in parental cells but not in CRR cells. DTX induced DNA double-strand breaks in parental cells. The mitochondrial membrane potential of CRR cells was lower in CRR cells than in parental cells. Depletion of mtDNA induced DTX resistance in parental cells. Treatment with dimethyl sulfoxide also induced DTX resistance in parental cells. Conclusions The mitochondrial dysfunction observed in CRR cells contributes to X-ray and DTX cross-resistance. The activation of oxidative phosphorylation in CRR cells may represent an effective approach to overcome radioresistant cancers. In general, the overexpression of β-tubulin or multidrug efflux pumps is thought to be involved in DTX resistance. In the present study, we discovered another DTX resistant mechanism by investigating CRR cells.

Original languageEnglish
Pages (from-to)556-565
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Issue number3
Publication statusPublished - 2016 Nov 1


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