T-type Ca2+ channel blocker, KYS05047 induces G1 phase cell cycle arrest by decreasing intracellular Ca2+ levels in human lung adenocarcinoma A549 cells

摘要

In a previous study, we found that the 3,4-dihydroquinazoline derivative, 4-(Benzylcarbamoylmethyl)-2-(biphenyl-4-ylamino)-3-(5-tert-butyloxycarbamoyl-1- pentyl)-3,4-dihydroquinazoline (KYS05047), was a selective T-type Ca 2+ channel blocker with anti-proliferative effects against various cancer cells. However, the mechanism responsible for its effects has not been studied. In this study, we investigated the effect of KYS05047 on cell cycle arrest and the mechanisms involved in human lung adenocarcinoma A549 cells. Among the G1 phase cell cycle-related proteins examined, the levels of cyclin-dependent protein kinase (Cdk2) and Cdk4 were reduced by KYS05047 (7 μM), whereas the steady-state levels of cyclin D1 and E were unaffected. In addition, KYS05047 increased the protein level of p27KIP1 and suppressed the kinase activities of Cdk2 and Cdk4. In addition, pretreatment with KCl, which increases intracellular Ca2+ levels, prevented KYS05047-induced intracellular Ca2+ decreases and cell cycle arrest. Furthermore, the administration of KYS05047 (2 or 10 mg/kg, po) for 21 days was also found to significantly inhibit tumor growth in an A549 xenograft nude mice model. In conclusion, our results suggested that KYS05047 induced G1 phase cell cycle arrest in A549 cells associated with a decrease in intracellular Ca2+ concentrations and inhibited the in vivo tumor growth of A549 xenograft mice.