Exploring the radiosensitizing potential of AZD8931: a pilot study on the human LoVo colorectal cancer cell line

摘要

Aim To explore the radiosensitizing effect of AZD8931, a novel equipotent and reversible inhibitor of signaling by EGFR (HER1), HER2 and HER3 receptors, focusing on cell cycle progression, apoptosis and clonogenic capacity in the human LoVo colorectal cancer (CRC) cell line, also in comparison with the EGFR-blocking monoclonal antibody Cetuximab or the EGFR tyrosine kinase selective small molecular inhibitor Gefitinib. Materials and methods Cells were pretreated with EGFR inhibitors for 5 consecutive days and then exposed or not to ionizing radiation (IR) (2 Gy daily for 3 consecutive days). Cell proliferation, cell cycle progression and apoptosis were evaluated by flow cytometry and enzyme-linked immunosorbent assay (ELISA), clonogenic potential and radiosensitivity were studied by colony formation assay. Results AZD8931 induced cell cycle arrest and apoptosis more effectively than Gefitinib and Cetuximab and, more importantly, it was significantly more potent than Gefitinib and Cetuximab in radiosensitizing cells. This radiosensitizing action by AZD8931 mainly occurred by markedly reducing cell cycle progression into S phase, the most radioresistant phase of cell cycle, secondly by inducing apoptosis and reducing clonogenic survival. Conclusions Our results show that AZD8931 increases IR efficacy in LoVo cells, suggesting that it works as a potent radiosensitizer, even more efficient than Gefitinib and Cetuximab, opening new pathways of investigation for further in vitro and in vivo studies aimed at confirming its potential to improve local radiotherapy in CRC.