In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers.
The growth inhibition of human cancer cells via T-type Ca(2+) channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca(2+) channel (Cav3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c-6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G1 phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca(2+) channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G1 phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca(2+) channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea.
Sun Jeong
SJ
Jang
Heung Woo
HW
Choi
Doo Li
DL
Choi
Sehyeon
S
Cho
Hong-Kun
HK
Rim
Hye-Eun
HE
Choi
Ki-Sun
KS
Kim
Minghua
M
Huang
Hyewhon
H
Rhim
Kyung-Tae
KT
Lee
Jae Yeol
JY
Lee
D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D020747:Calcium Channels, T-Type / Q000737:chemistry* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C549128:KYS 05090; D011799:Quinazolines
Apoptosis; Cell cycle arrest; Cytotoxicity; Ovarian cancer; T-type Ca(2+) channel