YSK2821, a newly synthesized indoledione derivative, inhibits cell proliferation and cell cycle progression via the cell cycle-related proteins by regulating phosphatidylinositol-3 kinase cascade in vascular smooth muscle cells.
Indoledione derivatives have pronounced biological effects, i.e., cytotoxic activities against cancer cell lines and antifungal and antibacterial activities. The present study was designed to investigate the effects of YSK2821, a newly synthesized indoledione derivative, on platelet-derived growth factor (PDGF-BB)-induced vascular smooth muscle cell (VSMC) proliferation, as well as the molecular mechanisms of the anti-proliferative effects of YSK2821 in VSMCs. We found that YSK2821 caused the accumulation of cells in the G1 phase of the cell cycle and inhibited [3H]-thymidine incorporation. We demonstrated that YSK2821 remarkably decreased Akt kinase phosphorylation as the mechanism by which YSK2821 suppressed cell signal transduction events in VSMC proliferation. Furthermore, in terms of the effects of YSK2821 on cell cycle-related proteins, YSK2821 enhanced the expression of the cyclin-dependent protein kinase (CDK) inhibitor p27 and down-regulated CDK2 and cyclin E expression, but did not affect CDK4 and cyclin D1 expression. YSK2821 also inhibited the phosphorylation of Rb, a key regulator in the cell cycle. These results indicate that YSK2821, a newly synthesized indoledione derivative, may inhibit VSMC proliferation via a phosphatidylinositol (PI)-3 kinase-dependent pathway, and thus shed light on a novel role for YSK2821 as a potential preventive regulator of cardiovascular disease.
Seo
Ji-Min
JM
College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University, Cheongju 361-763, Republic of Korea.
Kim
Tack-Joong
TJ
Jin
Yong-Ri
YR
Han
Hyeong-Jun
HJ
Ryu
Chung-Kyu
CK
Sheen
Yhun Y
YY
Kim
Dong-Woon
DW
Yun
Yeo-Pyo
YP
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009336:Necrosis / Q000139:chemically induced; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism
D018797:Cell Cycle Proteins; D010982:Platelet-Derived Growth Factor; D011758:Pyrroles; D015363:Quinolones; C531032:YSK 2821; D019869:Phosphatidylinositol 3-Kinases; D013936:Thymidine