Manumycin induces apoptosis in human hepatocellular carcinoma HepG2 cells.
Farnesyltransferase inhibitors (FTIs) were developed to prevent Ras processing and thus to be effective agents for the treatment of cancers harbouring mutated ras. In the present study, HepG2 cells underwent internucleosomal DNA fragmentation after treatment with farnesyltransferase inhibitor manumycin (20 microM) for 12 h. Flow cytometric analysis showed that HepG2 cells were accumulated in the G2/M phase of the cell cycle and the number of apoptotic sub-G1 fraction of cells was increased after treatment with manumycin in a time-dependent manner. During the induction of apoptosis, expression of p53 and p21WAF1 was upregulated, phosphorylation of IkappaB-alpha was blocked, caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B were cleaved, and Bcl-2 and Bax protein expression remained unchanged. These results indicated that manumycin induced apoptosis in HepG2 cells. The induction of apoptosis by manumycin involved the upregulation of p53 and p21WAF1, the activation of caspases, and the inhibition of nuclear factor-kappaB (NF-kappaB) pathway. However, Bcl-2 and Bax are not associated with manumycin-mediated apoptosis.
Zhou
Jun-Min
JM
Cancer Institute, Cancer Center, Sun Yat-sen University, 651 DongFeng Road East, Guangzhou 510060, China.
Zhu
Xiao-Feng
XF
Pan
Qi-Chao
QC
Liao
Duan-Fang
DF
Li
Zhi-Ming
ZM
Liu
Zong-Chao
ZC
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D018631:ras Proteins / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D018631:ras Proteins; C054474:manumycin