Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells.
A strategy to overcome radioresistance in cancer treatment has been expected. To evaluate the strategy, appropriate experimental models are needed. Radioresistant tumour models were originally established from human colon cancer cells, and we evaluated their molecular basis. Next, the growth inhibitory effects of newly synthesized vitamin K2 (VK2)-related compounds were tested. Here, we showed that these novel compounds 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 growth inhibitory activities of several chemical compounds. Radioresistant tumour models were established by fractionated radiation exposure. Irradiated cells were selected by a single cell cloning method, and their sensitivity to ionizing radiation was evaluated by a colony-forming assay. The VK2 derivatives (named MQ-1, MQ-2, and MQ-3) were chemically synthesized. To evaluate the generation of ROS, flow cytometer analyses were performed. A radioresistant tumour model was established from the HCT116 human colon cancer cell line. The radioresistant cells from HCT116 also showed resistance to cisplatin. In the radioresistant cells, NF-κB was highly activated. MQ-1, MQ-2, and MQ-3 showed greater growth inhibitory activities than VK2 not only in various cancer cells but also in radioresistant cells through the generation of ROS. In conclusion, a radioresistant tumour model was originally established from colon cancer cell lines through NF-κB activation, and it could be a useful tool for evaluating anti-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 findings together might pave the way for the treatment of radioresistant or recurrent cancers.
Divisions of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho Chuouku Kobe City, Hyogo 650-0017, Japan.
Helfi
H
Amalia
Ryohei
R
Sasaki
Yoko
Y
Suzuki
Yusuke
Y
Demizu
Toshinori
T
Bito
Hideki
H
Nishimura
Yoshiaki
Y
Okamoto
Kenji
K
Yoshida
Daisuke
D
Miyawaki
Tetsuya
T
Kawabe
Yoshiyuki
Y
Mizushina
Kazuro
K
Sugimura
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D024482:Vitamin K 2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D016328:NF-kappa B; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D024482:Vitamin K 2