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

Abstract

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 (ρ{sup 0}) 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: Themore » 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.« less

Authors:
 [1]; ; ; ;  [2];  [3];  [2]
  1. Department of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai (Japan)
  2. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai (Japan)
  3. Department of Radiopharmacy, Tohoku Medical and Pharmaceutical University, Sendai (Japan)
Publication Date:
OSTI Identifier:
22645675
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 96; Journal Issue: 3; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; 63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; ANTINEOPLASTIC DRUGS; GY RANGE 01-10; MEMBRANES; MITOCHONDRIA; NEOPLASMS; RADIOSENSITIVITY; RADIOTHERAPY; STRAND BREAKS

Citation Formats

Kuwahara, Yoshikazu, Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Roudkenar, Mehryar Habibi, Suzuki, Masatoshi, Urushihara, Yusuke, Fukumoto, Motoi, Saito, Yohei, Fukumoto, Manabu, and Department of Molecular Pathology, Tokyo Medical University, Tokyo. The Involvement of Mitochondrial Membrane Potential in Cross-Resistance Between Radiation and Docetaxel. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.07.002.
Kuwahara, Yoshikazu, Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Roudkenar, Mehryar Habibi, Suzuki, Masatoshi, Urushihara, Yusuke, Fukumoto, Motoi, Saito, Yohei, Fukumoto, Manabu, & Department of Molecular Pathology, Tokyo Medical University, Tokyo. The Involvement of Mitochondrial Membrane Potential in Cross-Resistance Between Radiation and Docetaxel. United States. doi:10.1016/J.IJROBP.2016.07.002.
Kuwahara, Yoshikazu, Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Roudkenar, Mehryar Habibi, Suzuki, Masatoshi, Urushihara, Yusuke, Fukumoto, Motoi, Saito, Yohei, Fukumoto, Manabu, and Department of Molecular Pathology, Tokyo Medical University, Tokyo. Tue . "The Involvement of Mitochondrial Membrane Potential in Cross-Resistance Between Radiation and Docetaxel". United States. doi:10.1016/J.IJROBP.2016.07.002.
@article{osti_22645675,
title = {The Involvement of Mitochondrial Membrane Potential in Cross-Resistance Between Radiation and Docetaxel},
author = {Kuwahara, Yoshikazu and Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai and Roudkenar, Mehryar Habibi and Suzuki, Masatoshi and Urushihara, Yusuke and Fukumoto, Motoi and Saito, Yohei and Fukumoto, Manabu and Department of Molecular Pathology, Tokyo Medical University, Tokyo},
abstractNote = {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 (ρ{sup 0}) 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.},
doi = {10.1016/J.IJROBP.2016.07.002},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 3,
volume = 96,
place = {United States},
year = {2016},
month = {11}
}