SN-38 Acts as a Radiosensitizer for Colorectal Cancer by Inhibiting the Radiation-induced Up-regulation of HIF-1α

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)-1 alpha in the human colorectal cancer (CRC) cells. Materials and Methods: HT29 and SW480 cells were cultured with SN-38 (0-4,mu M) immediately after irradiation (0-8 Gy). HIF-1 alpha 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. Results: Radiation up-regulated HIF-1 alpha, and SN-38 inhibited the radiation-induced HIF-1 alpha. 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(2)/M cell-cycle arrest and decreased the population of cells in G(1). Conclusion: SN-38 inhibits the radiation-induced up-regulation of HIF-1 alpha and acts as a radiosensitizer by inducing cell-cycle arrest in CRC cells.