Seok Soon Park1, Young-Jong Kim2, Eun Jin Ju1, Seol Hwa Shin1, Jinhyang Choi1, Jaesook Park1, Jae Hee Lee1, Kyoung Jin Lee1, Jin Park1, Hye Ji Park1, Eun Jung Ko1, Jung Jin Hwang3, Dong-Hoon Jin1, Nayoung Suh4, Dong-Hyung Cho2, Jung Shin Lee5, Si Yeol Song6, B Moon Kim7, Seong-Yun Jeong8, Eun Kyung Choi9. 1. Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 2. Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea. 3. Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 4. Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 5. Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 6. Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 7. Department of Chemistry, Seoul National University, Republic of Korea. Electronic address: kimbm@snu.ac.kr. 8. Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: syj@amc.seoul.kr. 9. Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Development and Commercialization of Anti-cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: ekchoi@amc.seoul.kr.
Abstract
BACKGROUND AND PURPOSE: Ibulocydine (IB), a novel prodrug of CDK inhibitor, has been reported to have anti-cancer effect in human hepatoma cells. In order to address its feasibility as a radiosensitizer to improve radiotherapeutic efficacy for human cancers, this study was designed. MATERIAL AND METHODS: Human cancer cells of lung and colon were treated with IB and/or radiotherapy (RT). The cellular effects were assessed by CCK-8, clonogenic, flow cytometric, and western blotting assays. In vivo radiotherapeutic efficacy was evaluated using the xenograft mouse model. RESULTS: Combined treatment of IB and RT significantly reduced viability and survival fraction of the cells. Apoptotic cell death accompanied with activation of caspases, decrease in Bcl-2/Bax expression, loss of mitochondrial membrane potential (MMP) leading to release of cytochrome c into cytosol was observed. Recovery of Bcl-2 expression level by introducing Bcl-2 expressing plasmid DNA compromised the loss of MMP and apoptosis induced by IB and RT. In vivo therapeutic efficacy of combined treatment was verified in the xenograft mouse model, in which tumor growth was markedly delayed by RT with IB. CONCLUSIONS: IB demonstrated the property of sensitizing human cancer cells to RT by induction of mitochondria-mediated apoptosis, suggesting that IB deserves to be applied for chemoradiotherapy.
BACKGROUND AND PURPOSE:Ibulocydine (IB), a novel prodrug of CDK inhibitor, has been reported to have anti-cancer effect in humanhepatoma cells. In order to address its feasibility as a radiosensitizer to improve radiotherapeutic efficacy for humancancers, this study was designed. MATERIAL AND METHODS:Humancancer cells of lung and colon were treated with IB and/or radiotherapy (RT). The cellular effects were assessed by CCK-8, clonogenic, flow cytometric, and western blotting assays. In vivo radiotherapeutic efficacy was evaluated using the xenograft mouse model. RESULTS: Combined treatment of IB and RT significantly reduced viability and survival fraction of the cells. Apoptotic cell death accompanied with activation of caspases, decrease in Bcl-2/Bax expression, loss of mitochondrial membrane potential (MMP) leading to release of cytochrome c into cytosol was observed. Recovery of Bcl-2 expression level by introducing Bcl-2 expressing plasmid DNA compromised the loss of MMP and apoptosis induced by IB and RT. In vivo therapeutic efficacy of combined treatment was verified in the xenograft mouse model, in which tumor growth was markedly delayed by RT with IB. CONCLUSIONS:IB demonstrated the property of sensitizing humancancer cells to RT by induction of mitochondria-mediated apoptosis, suggesting that IB deserves to be applied for chemoradiotherapy.