2. Academic Validation
  3. In vitro synergistic anticancer activity of the combination of T-type calcium channel blocker and chemotherapeutic agent in A549 cells

In vitro synergistic anticancer activity of the combination of T-type calcium channel blocker and chemotherapeutic agent in A549 cells

  • Bioorg Med Chem Lett. 2016 Feb 1;26(3):1073-1079. doi: 10.1016/j.bmcl.2015.12.010.
Joon Seok Byun 1,  Joo Mi Sohn 1,  Dong Gyu Leem 2,  Byeongyeon Park 1,  Ji Hye Nam 1,  Dong Hyun Shin 2,  Ji Sun Shin 2,  Hyoung Ja Kim 3,  Kyung-Tae Lee 4,  Jae Yeol Lee 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 3 Molecular Recognition Research Center, Future Convergence Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 4 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.
  • 5 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.
PMID: 26739776 DOI: 10.1016/j.bmcl.2015.12.010
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.

Keywords

Apoptosis; Cell cycle arrest; Human lung cancer; Synergistic effect; T-type calcium channel.

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