Antiproliferative effects of 6-anilino-5-chloro-1H-benzo[d]imidazole-4,7-dione in vascular smooth muscle cells.
It has been known that benzimidazol-4,7-diones have antiproliferative activity against various cancer cell lines. Recently, we have also reported that these compounds strongly inhibited the proliferation of vascular smooth muscle cell (SMC) and human umbilical vein endothelial cells (HUVECs). Although benzimidazol-4,7-diones have important biological activities, the molecular mechanism of the compounds in these cells remains to be elucidated. In order to investigate the anti-proliferation mechanism of the compounds in smooth muscle cell, we selected 6-anilino-6-chloro-5-chloro-1H-benzo{d}midazole-4,7-dione (BUD-0203) among 12 benzimidazol-4,7-dione derivatives and examined its antiproliferative effects. Phosphorylation of the extracellular-signal regulated kinase (ERK) reached a maximal level at 1h after treatment with BUD-0203 and was sustained during the examined period. We also observed that phosphorylation of p38 reached a maximal level at 4h and decreased to control levels after 8h. These results showed that BUD-0203 sustainedly activated MAP kinase pathways in SMC. However, this compound did not induce cell cycle arrest in G1 or G2 phase in these cells. We also demonstrated that BUD-0203 not only induced apoptosis of SMC, but it also strongly inhibited SMC migration induced by platelet-derived growth factor (PDGF) or serum. Taken together, our experiments indicate that benzimidazol-4,7-diones induce apoptosis of smooth muscle cell via simultaneously prolonged activation of MAP kinase pathways including ERK, p38, and JNK/SAPK, similar with the apoptosis mechanism reported previously.
Hong
Sung-Yu
SY
National Research Laboratory for Cardiovascular Therapy, BioBud Inc., Geumchen-gu, Seoul 153-777, Republic of Korea.
Kwak
Kyu-Won
KW
Ryu
Chung-Kyu
CK
Kang
Soo-Jung
SJ
Chung
Kwang-Hoe
KH
D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
C526394:6-anilino-5-chloro-1H-benzo(d)imidazole-4,7-dione; D001562:Benzimidazoles; D020928:Mitogen-Activated Protein Kinases