Ibulocydine sensitizes human cancers to radiotherapy by induction of mitochondria-mediated apoptosis

• Published in: Radiotherapy and oncology 2014-08, Vol.112 (2), p.295-301
• Main Authors: Park, Seok Soon, Kim, Young-Jong, Ju, Eun Jin, Shin, Seol Hwa, Choi, Jinhyang, Park, Jaesook, Lee, Jae Hee, Lee, Kyoung Jin, Park, Jin, Park, Hye Ji, Ko, Eun Jung, Hwang, Jung Jin, Jin, Dong-Hoon, Suh, Nayoung, Cho, Dong-Hyung, Lee, Jung Shin, Song, Si Yeol, Kim, B. Moon, Jeong, Seong-Yun, Choi, Eun Kyung
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Bcl-2; Caspase; Caspases - metabolism; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - radiotherapy; Cytochromes c - metabolism; Flow Cytometry; Hematology, Oncology and Palliative Medicine; Humans; Ibulocydine; Lung Neoplasms - drug therapy; Lung Neoplasms - radiotherapy; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - radiation effects; Proto-Oncogene Proteins c-bcl-2; Pyrimidine Nucleosides - pharmacology; Radiation-Sensitizing Agents - pharmacology; Radiotherapy; Xenograft Model Antitumor Assays
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2014.07.005

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.