Zhou Jun-Min, Zhu Xiao-Feng, Pan Qi-Chao, Liao Duan-Fang, Li Zhi-Ming, Liu Zong-Chao
Cancer Institute, Cancer Center, Sun Yat-sen University, 651 DongFeng Road East, Guangzhou 510060, China.
Int J Mol Med. 2003 Dec;12(6):955-9.
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.
法尼基转移酶抑制剂（FTIs）的研发目的是阻止Ras蛋白的加工过程，从而成为治疗携带ras基因突变癌症的有效药物。在本研究中，HepG2细胞在用法尼基转移酶抑制剂马尼霉素（20微摩尔）处理12小时后发生了核小体间DNA片段化。流式细胞术分析表明，HepG2细胞在细胞周期的G2/M期积累，用马尼霉素处理后，凋亡亚G1期细胞数量呈时间依赖性增加。在诱导凋亡过程中，p53和p21WAF1的表达上调，IκB-α的磷酸化被阻断，半胱天冬酶底物聚（ADP-核糖）聚合酶（PARP）和核纤层蛋白B被切割，而Bcl-2和Bax蛋白表达保持不变。这些结果表明马尼霉素可诱导HepG2细胞凋亡。马尼霉素诱导凋亡涉及p53和p21WAF1的上调、半胱天冬酶的激活以及核因子κB（NF-κB）通路的抑制。然而，Bcl-2和Bax与马尼霉素介导的凋亡无关。
