Dai Xiao-Yun, Zeng Xiu-Xiu, Peng Feng, Han Yuan-Yuan, Lin Hong-Jun, Xu You-Zhi, Zhou Tian, Xie Gang, Deng Yi, Mao Yong-Qiu, Yu Luo-Ting, Yang Li, Zhao Ying-Lan
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Cell Physiol Biochem. 2012;29(1-2):281-90. doi: 10.1159/000337609. Epub 2012 Mar 1.
Hepatocellular carcinoma is one of the most common cancers in worldwide. We previously reported a novel thienopyridine derivative 3-amino-6-(3,4-dichlorophenyl) thieno[2,3-b]pyridine-2-carboxamide (SKLB70359) which possesses anticancer activity against hepatocellular carcinoma. In present study, we further investigated its anticancer activity and possible mechanism. The SKLB70359 treatment decreased the viability of a panel of hepatocellular carcinoma cell lines in a concentration- and time-dependent manner with IC(50) 0.4 ~ 2.5 μM. The mechanism study showed that SKLB70359 induced G0/G1 cell cycle arrest and then led to apoptotic cell death of HepG2 cell. The SKLB70359 induced G0/G1 cell cycle arrest was characterized by down-regulation of cyclin-dependent kinase 2 (CDK2), CDK4, CDK6 expression and up-regulation of p53, p21(WAF1). Activating of caspase-3 and caspase-9 was also observed. Meanwhile, proliferation inhibitory effect of SKLB70359 was associated with decreased level of phosphorylated p44/42 mitogen activated protein kinase (p44/42 MAPK) and phosphorylated retinoblastoma protein (Rb). Moreover, SKLB70359 exhibit less toxicity to non-cancer cells than tumor cells. In conclusion, the findings in this study suggested that SKLB70359 have potential anticancer efficacy via G0/G1 cell cycle arrest and apoptosis induction. Its potential to be a candidate of anticancer agent is worth being further investigated.
肝细胞癌是全球最常见的癌症之一。我们之前报道了一种新型噻吩并吡啶衍生物3-氨基-6-(3,4-二氯苯基)噻吩并[2,3-b]吡啶-2-甲酰胺(SKLB70359)，它对肝细胞癌具有抗癌活性。在本研究中，我们进一步研究了其抗癌活性及可能的机制。SKLB70359处理以浓度和时间依赖性方式降低了一组肝癌细胞系的活力，IC(50)为0.4~2.5μM。机制研究表明，SKLB70359诱导G0/G1细胞周期阻滞，进而导致HepG2细胞凋亡。SKLB70359诱导的G0/G1细胞周期阻滞的特征是细胞周期蛋白依赖性激酶2(CDK2)、CDK4、CDK6表达下调，p53、p21(WAF1)表达上调。还观察到半胱天冬酶-3和半胱天冬酶-9的激活。同时，SKLB70359的增殖抑制作用与磷酸化p44/42丝裂原活化蛋白激酶(p44/42 MAPK)和磷酸化视网膜母细胞瘤蛋白(Rb)水平降低有关。此外，SKLB70359对非癌细胞的毒性低于肿瘤细胞。总之，本研究结果表明，SKLB70359通过G0/G1细胞周期阻滞和诱导凋亡具有潜在的抗癌疗效。其作为抗癌药物候选物的潜力值得进一步研究。
