Okuno Takayuki, Kawai Kazushige, Hata Keisuke, Murono Koji, Emoto Shigenobu, Kaneko Manabu, Sasaki Kazuhito, Nishikawa Takeshi, Tanaka Toshiaki, Nozawa Hiroaki
Department of Surgical Oncology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
Department of Surgical Oncology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Anticancer Res. 2018 Jun;38(6):3323-3331. doi: 10.21873/anticanres.12598.
BACKGROUND/AIM: Hypoxia offers resistance to therapy in human solid tumors. The aim of the study was to investigate whether SN-38, the active metabolite of irinotecan, acts as a radiosensitizer through inhibition of hypoxia-inducible factor (HIF)-1α in the human colorectal cancer (CRC) cells.
HT29 and SW480 cells were cultured with SN-38 (0-4 μM) immediately after irradiation (0-8 Gy). HIF-1α expression was assessed using flow-cytometry and western blot analysis. Cell proliferation was evaluated by the calcein assay. Apoptosis and cell cycle were determined by flow-cytometry.
Radiation up-regulated HIF-1α, and SN-38 inhibited the radiation-induced HIF-1α. The combination of radiation and SN-38 inhibited cell proliferation more than radiation alone; treatment with SN-38 after radiation exposure did not increase the number of apoptotic cells, whereas, it enhanced the S and G/M cell-cycle arrest and decreased the population of cells in G Conclusion: SN-38 inhibits the radiation-induced up-regulation of HIF-1α and acts as a radiosensitizer by inducing cell-cycle arrest in CRC cells.
背景/目的：缺氧使人类实体瘤对治疗产生抗性。本研究的目的是调查伊立替康的活性代谢产物SN - 38是否通过抑制人结肠癌细胞（CRC）中的缺氧诱导因子（HIF）-1α发挥放射增敏剂的作用。
HT29和SW480细胞在照射（0 - 8 Gy）后立即用SN - 38（0 - 4 μM）培养。使用流式细胞术和蛋白质印迹分析评估HIF - 1α的表达。通过钙黄绿素测定评估细胞增殖。通过流式细胞术确定细胞凋亡和细胞周期。
辐射上调HIF - 1α，而SN - 38抑制辐射诱导的HIF - 1α。辐射与SN - 38联合使用比单独辐射更能抑制细胞增殖；辐射暴露后用SN - 38处理并未增加凋亡细胞数量，然而，它增强了S期和G/M期细胞周期阻滞并减少了G期细胞群体。结论：SN - 38抑制辐射诱导的HIF - 1α上调，并通过诱导CRC细胞的细胞周期阻滞发挥放射增敏剂的作用。
