title: In vitro synergistic anticancer activity of the combination of T-type calcium channel blocker and chemotherapeutic agent in A549 cells.
abstract: As a result of our continuous research, new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F was synthesized and evaluated for T-type Ca(2+) channel (Cav3.1) blockade, cytotoxicity, and cell cycle arrest against human non-small cell lung (A549) cells. KCP10043F showed both weaker T-type Ca(2+) channel blocking activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N',N'-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27(KIP1) as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index=0.2-0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer.
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Joon Seok
authors.initials: JS
authors.lastname: Byun
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Joo Mi
authors.initials: JM
authors.lastname: Sohn
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Dong Gyu
authors.initials: DG
authors.lastname: Leem
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Byeongyeon
authors.initials: B
authors.lastname: Park
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Nam
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Ji Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Molecular Recognition Research Center, Future Convergence Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
authors.forename: Hyoung Ja
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ljy@khu.ac.kr.
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D016213:Cyclins; C549128:KYS 05090; D011799:Quinazolines; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases
keywords: Apoptosis; Cell cycle arrest; Human lung cancer; Synergistic effect; T-type calcium channel