Vitamin K2-derived Compounds Induce Growth Inhibition in Radioresistant Cancer Cells

摘要

A strategy to overcome radioresistance in cancer treatment has been expected. Toevaluate the strategy, appropriate experimental models are needed. Radioresistanttumour models were originally established from human colon cancer cells, and weevaluated their molecular basis. Next, the growth inhibitory effects of newly synthesizedvitamin K2 (VK2)-related compounds were tested. Here, we showed that these novelcompounds have growth inhibitory effects not only on cancer cells of various origins,but also on radioresistant cells, through the generation of reactive oxygen species(ROS).Human colon, lung, and breast cancer cell lines were used for testing the growthinhibitory activities of several chemical compounds. Radioresistant tumour modelswere established by fractionated radiation exposure. Irradiated cells were selected by asingle cell cloning method, and their sensitivity to ionizing radiation was evaluated by acolony-forming assay. The VK2 derivatives (named MQ-1, MQ-2, and MQ-3) werechemically synthesized. To evaluate the generation of ROS, flow cytometer analyseswere performed.A radioresistant tumour model was established from the HCT116 human coloncancer cell line. The radioresistant cells from HCT116 also showed resistance tocisplatin. In the radioresistant cells, NF-êB was highly activated. MQ-1, MQ-2, andMQ-3 showed greater growth inhibitory activities than VK2 not only in various cancercells but also in radioresistant cells through the generation of ROS.In conclusion, a radioresistant tumour model was originally established from coloncancer cell lines through NF-êB activation, and it could be a useful tool for evaluatinganti-tumour agents. Newly synthesized VK2 derivatives (MQ-1, MQ-2 and MQ-3)seemed to be potential anti-tumour agents in various cancers and radioresistant cancers.The efficacy of those compounds was related to the generation of ROS. These findingstogether might pave the way for the treatment of radioresistant or recurrent cancers.