Asiatic acid, a triterpene, induces apoptosis through intracellular Ca2+ release and enhanced expression of p53 in HepG2 human hepatoma cells.
Asiatic acid (AA), a triterpene, decreased viability and induced apoptosis of HepG2 human hepatoma cells in a dose-dependent manner. AA also markedly increased intracellular Ca(2+) level, which was blocked by TMB-8 and dantrolene, intracellular Ca(2+) release blockers, but not by EGTA, an extracellular Ca(2+) chelator. Moreover, AA-induced apoptosis was significantly suppressed by treatment with TMB-8 and dantrolene, suggesting that intracellular Ca(2+) release may play an essential role in the AA-induced apoptosis. In addition, AA profoundly increased protein level of p53, which was also inhibited by BAPTA/AM, an intracellular Ca(2+) chelator, TMB-8 and dantrolene. Treatment with A23187, a Ca(2+) ionophore, or thapsigargin, a Ca(2+)-ATPase inhibitor, alone enhanced p53 nuclear accumulation, indicating that p53 accumulation is dependent on intracellular Ca(2+) increase. Furthermore, the viability of Hep3B, p53-null cells, was much higher than that of HepG2, p53-wild type cells, when treated with AA. Taken together, these results suggest that AA induced apoptosis through increased intracellular Ca(2+), which, in turn, enhanced p53 expression in HepG2 cells. These results further suggest that AA may be a valuable agent for the therapeutic intervention of human hepatomas.
College of Pharmacy, Duksung Women's University, Seoul 132-714, South Korea.
Yong Soo
YS
Lee
Da-Qing
DQ
Jin
Eun Jin
EJ
Kwon
Seung Hee
SH
Park
Eung-Seok
ES
Lee
Tae Cheon
TC
Jeong
Doo Hyun
DH
Nam
Keun
K
Huh
Jung-Ae
JA
Kim
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; C017032:asiatic acid; D002118:Calcium