Download Quinacrine increases radiosensitivity of cancer cells under hypoxia

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Quinacrine increases radiosensitivity of cancer cells under hypoxia
Chong Han Kim1,2, Ha Gyeong Kim1, Eun-Taex Oh2,3,4, Chan Woo Kim1, Jung-A Choi1, Hong-Seok
Kim3,5 and Heon Joo Park1,2,3,*
1
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of
Korea, 2Center for Bio-Nano technology to improve radiotherapy, Inha University, Incheon 22212,
Republic of Korea, 3Hypoxia-related Disease Research Center, Inha University School of Medicine,
Incheon 22212, Republic of Korea, 4Department of Biomedical Sciences, College of Medicine, Inha
University, Incheon 22212, Republic of Korea, 5Department of Molecular Medicine, Inha University,
Incheon 22212, Republic of Korea
In the cancer therapy, the resistance of hypoxic cells to radiotherapy is a major problem. In addition,
there has been a growing interest in using hypoxia inducible factor-1α (HIF-1α) inhibitors as a
radiosensitizer. Recently, quinacrine, which is approved by the FDA for treatment of malaria, has been
reported to increase radiosensitivity in cancer cells under normoxia, but its molecular mechanism in
hypoxic cancer cells is unclear. The purpose of this study was to examine the quinacrine-induced cell
death and radiosensitization in cancer cells under hypoxia. The radiosensitizing effect of quinacrine
under hypoxic (<0.5%) condition was assessed with analysis of apoptotic cell death using flow
cytometry, analysis of cell proliferation, and clonogenic survival assay. The effect of quinacrine on the
molecular mechanism underlying suppression of Nrf2 and HIF-1α was analyzed with Western blotting
and promoter assay. Quinacrine dose-dependently increased radiosensitivity in cancer cells under
hypoxia. With luciferase reporter assay and Western blotting, we observed that quinacrine inhibited
expression of HIF-1α by inhibiting expression of Nrf2 in cancer cells under hypoxia. Our results
collectively show that, under hypoxia, quinacrine contributes to increase radiosensitivity of cancer
cells under hypoxia by inhibiting Nrf2-mediated increase of HIF-1α. [NRF-2013M2A2A7043703,
NRF-2014R1A5A2009392, and NRF-2015M2B2B1068599].