Cell cycle arrest and cytochrome c-mediated apoptotic induction in human lung cancer A549 cells by MCS-C2, an analogue of sangivamycin.
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.
Kang
Jeonghwa
J
Department of Medical Genetics, College of Medicine, Hanyang University, Seoul 133-791, Korea.
Lee
Dong-Keun
DK
Lee
Chul-Hoon
CH
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D014127:Toyocamycin / Q000031:analogs & derivatives* / Q000494:pharmacology
C502156:MCS-C2; D011741:Pyrimidine Nucleosides; C005699:sangivamycin; D045304:Cytochromes c; D014127:Toyocamycin