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Cell cycle arrest and cytochrome c-mediated apoptotic induction in human lung cancer A549 cells by MCS-C2, an analogue of sangivamycin.

Abstract
In the course of our screening for novel modulators on cell cycle progression and apoptosis as anticancer drug candidates, we generated an analogue of sangivamycin, MCS-C2, designated as 4-amino-6-bromo-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. This study was aimed to evaluate the molecular mechanisms on cell cycle arrest and apoptotic induction of MCS-C2 in human lung cancer A549 cells. To investigate the effects of MCS-C2 on cell cycle progression in A549 cells, we measured DNA content of A549 cells treated with 5 microM of HY253 using flow cytometric analysis. The flow cytometric analysis revealed an appreciable G(2) phase arrest in A549 cells treated with 5 micronM of MCS-C2. This MCS-C2-induced G(2) phase arrest is associated with significant up-regulation of p53 and p21(Cip1) in A549 cells. Furthermore, TUNEL assay was used to examine apoptotic induction in A549 cells treated with 5 microM of MCS-C2 for 48 h. In addition, the effects of MCS-C2 on apoptosis-associated proteins in A549 cells were examined using Western blot analysis. The apoptotic induction in MCS-C2-treated A549 cells is associated with cytochrome c release from mitochondria which in turn resulted in the activation of caspase-9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). In conclusion, based on these results, we suggest that MCS-C2 may be a potent cancer chemotherapeutic candidate for use in treating human lung cancer cells via up-regulation and activation of p53.
AuthorsJeonghwa Kang, Dong-Keun Lee, Chul-Hoon Lee
JournalJournal of microbiology and biotechnology (J Microbiol Biotechnol) Vol. 20 Issue 2 Pg. 433-7 (Feb 2010) ISSN: 1017-7825 [Print] Korea (South)
PMID20208452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • MCS-C2
  • Pyrimidine Nucleosides
  • sangivamycin
  • Cytochromes c
  • Toyocamycin
Topics
  • Apoptosis (drug effects)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cytochromes c (metabolism)
  • Humans
  • Lung Neoplasms (drug therapy, metabolism, physiopathology)
  • Pyrimidine Nucleosides (pharmacology)
  • Toyocamycin (analogs & derivatives, pharmacology)

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