Yang Lehe, Li Jifa, Xu Lingyuan, Lin Shichong, Xiang Youqun, Dai Xuanxuan, Liang Guang, Huang Xiaoying, Zhu Jiandong, Zhao Chengguang
Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China,
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China,
Cancer Manag Res. 2019 Feb 1;11:1167-1176. doi: 10.2147/CMAR.S171517. eCollection 2019.
Non-small-cell lung cancer (NSCLC) comprises about 85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. The IL-6/STAT3 signaling pathway plays a pivotal role in NSCLC biology. Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that Rhein has significant antitumor effects, supporting the potential uses of Rhein as an antitumor agent.
Cell viability and colony formation were performed to examine Rhein's potent anti-proliferative effect in human NSCLC cell lines PC-9, H460 and A549. Flow cytometry-based assay was employed to study whether Rhein could affect cell apoptosis and cycle. The expression level of P-STAT3, apoptosis and cycle-related proteins Bcl-2, Bax, MDM2, CDC2, P53 and CyclinB1 were detected by Western blotting. The xenograft models were used to evaluate the in vivo effect of Rhein.
We found that Rhein could significantly reduce the viability and stimulate apoptosis in human NSCLC cells in a dose-dependent manner. Western blot analysis results suggested that the antitumor effect of Rhein might be mediated via STAT3 inhibition. Rhein upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. In addition, Rhein induced the arrest of NSCLC cells in the G2/M phase of the cell cycle and dose dependently inhibited the expression of cycle-related proteins. The Rhein also inhibited tumor growth in H460 xenograft models.
Rhein shows potent efficacy against NSCLC through inhibiting the STAT3 pathway. Our results also suggest that Rhein has a promising potential to be used as a novel antitumor agent for the treatment of NSCLC.
非小细胞肺癌（NSCLC）约占所有肺癌的85%，通常在晚期被诊断出来，预后较差。白细胞介素-6/信号转导和转录激活因子3（IL-6/STAT3）信号通路在NSCLC生物学中起关键作用。大黄酸是一种广泛存在于草药中的亲脂性蒽醌。新出现的证据表明，大黄酸具有显著的抗肿瘤作用，支持其作为抗肿瘤药物的潜在用途。
进行细胞活力和集落形成实验，以检测大黄酸对人NSCLC细胞系PC-9、H460和A549的强大抗增殖作用。采用基于流式细胞术的检测方法研究大黄酸是否会影响细胞凋亡和周期。通过蛋白质免疫印迹法检测磷酸化STAT3、凋亡和周期相关蛋白Bcl-2、Bax、MDM2、细胞周期蛋白依赖性激酶2（CDC2）、P53和细胞周期蛋白B1的表达水平。使用异种移植模型评估大黄酸的体内作用。
我们发现大黄酸可以显著降低人NSCLC细胞的活力，并以剂量依赖的方式刺激细胞凋亡。蛋白质免疫印迹分析结果表明，大黄酸的抗肿瘤作用可能是通过抑制STAT3介导的。大黄酸上调促凋亡蛋白Bax的表达，下调抗凋亡蛋白Bcl-2的表达。此外，大黄酸诱导NSCLC细胞在细胞周期的G2/M期停滞，并剂量依赖性地抑制周期相关蛋白的表达。大黄酸还抑制了H460异种移植模型中的肿瘤生长。
大黄酸通过抑制STAT3通路对NSCLC显示出强大的疗效。我们的结果还表明，大黄酸有潜力作为一种新型抗肿瘤药物用于治疗NSCLC。
