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Inhibition of cellular proliferation and induction of apoptosis in human lung adenocarcinoma A549 cells by T-type calcium channel antagonist.

Abstract
The anti-proliferative and apoptotic activities of new T-type calcium channel antagonist, 6e (BK10040) on human lung adenocarcinoma A549 cells were investigated. The MTT assay results indicated that BK10040 was cytotoxic against human lung adenocarcinoma (A549) and pancreatic cancer (MiaPaCa2) cells in a dose-dependent manner with IC50 of 2.25 and 0.93μM, respectively, which is ca. 2-fold more potent than lead compound KYS05090 despite of its decreased T-type calcium channel blockade. As a mode of action for cytotoxic effect of BK10040 on lung cancer (A549) cells, this cancer cell death was found to have the typical features of apoptosis, as evidenced by the accumulation of positive cells for annexin V. In addition, BK10040 triggered the activations of caspases 3 and 9, and the cleavages of poly (ADP-ribose) polymerase (PARP). Moreover, the treatment with z-VAD-fmk (a broad spectrum caspase inhibitor) significantly prevented BK10040-induced apoptosis. Based on these results, BK10040 may be used as a potential therapeutic agent for human lung cancer via the potent apoptotic activity.
AuthorsDoo Li Choi, Sun Jeong Jang, Sehyeon Cho, Hye-Eun Choi, Hong-Kun Rim, Kyung-Tae Lee, Jae Yeol Lee
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 6 Pg. 1565-70 (Mar 15 2014) ISSN: 1464-3405 [Electronic] England
PMID24529871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • BK10040
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • KYS 05090
  • Piperazines
  • Quinazolines
Topics
  • Adenocarcinoma (metabolism, pathology)
  • Adenocarcinoma of Lung
  • Apoptosis (drug effects)
  • Calcium Channel Blockers (chemical synthesis, chemistry, pharmacology)
  • Calcium Channels, T-Type (chemistry, metabolism)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms (metabolism, pathology)
  • Piperazines (chemical synthesis, chemistry, pharmacology)
  • Quinazolines (chemical synthesis, chemistry, pharmacology)

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