T-type Ca2+ channel blocker, KYS05047 induces G1 phase cell cycle arrest by decreasing intracellular Ca2+ levels in human lung adenocarcinoma A549 cells.
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 G(1) 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 p27(KIP1) and suppressed the kinase activities of Cdk2 and Cdk4. In addition, pretreatment with KCl, which increases intracellular Ca(2+) levels, prevented KYS05047-induced intracellular Ca(2+) 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 G(1) phase cell cycle arrest in A549 cells associated with a decrease in intracellular Ca(2+) concentrations and inhibited the in vivo tumor growth of A549 xenograft mice.
Department of Pharmaceutical Biochemistry, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
Hong-Kun
HK
Rim
Heon-Woo
HW
Lee
Il Sook
IS
Choi
Jin Yeong
JY
Park
Heung Woo
HW
Choi
Jung-Hye
JH
Choi
Young-Wuk
YW
Cho
Jae Yeol
JY
Lee
Kyung-Tae
KT
Lee
D000230:Adenocarcinoma / Q000188:drug therapy; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous
C579646:4-(benzylcarbamoylmethyl)-2-(biphenyl-4-ylamino)-3-(5-tert-butyloxycarbamoyl-1-pentyl)-3,4-dihydroquinazoline; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D011799:Quinazolines; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D002118:Calcium