Cell cycle arrest and cytochrome c-mediated apoptotic induction by MCS-5A is associated with up-regulation of p16(INK4a) in HL-60 cells.
MCS-5A, an analog of sangivamycin, selectively inhibits the cyclin-dependent kinases CDK1 and 4 in HL-60 cells in vitro (IC(50): 9.6 and 8.8 1V, respectively), while weakly inhibiting other housekeeping protein kinases. MCS-5A effectively induces HL-60 cell cycle arrest at the G(1) and G(2)/M phases through direct inhibition of CDK1 and 4 activity. In addition, elevated expression of p16(INK4a) and a reduction in the level of hyperphosphorylated pRb showed that 3 1V MCS-5A also induces p16(INK4a)-mediated cell cycle arrest at the G(1) phase. Furthermore, apoptotic induction in MCS-5A-treated HL-60 cells is associated with the release of cytochrome c from mitochondria, which, in turn, results in the activation of procaspase-8, -9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the involvement of p16(INK4a) in this apoptotic induction was demonstrated using A549 cells with a homozygous deletion of p16(INK4a). Based on these results, we conclude that MCS-5A is a candidate therapeutic agent for the treatment of human promyelocytic leukemia via the up-regulation of p16(INK4a).
Choi
Bu Young
BY
Department of Molecular Biology & Pharmacology, Kyunggi-Do, Republic of Korea.
Lee
Chul-Hoon
CH
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
C547380:4-amino-6-bromo-7-(xylofuranosyl)pyrrolo(2,3-d)pyrimidine-5-carboxamide; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009705:Nucleosides; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases