Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Building 11, Chashan Street, University Town, Wenzhou, Zhejiang, 325035, People's Republic of China.
Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, People's Republic of China.
J Exp Clin Cancer Res. 2019 Jan 23;38(1):31. doi: 10.1186/s13046-018-1015-9.
Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics.
The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis.
Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants.
Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.
大黄酸是一种广泛存在于药用植物中的脂溶性蒽醌。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。IL6/STAT3 信号通路已被认为是发现新型癌症治疗药物的有吸引力的靶点。
选择人胰腺癌细胞系 AsPC-1、Patu8988T、BxPC-3 和 PANC-1 以及免疫缺陷小鼠作为模型，研究大黄酸的作用。通过细胞活力、细胞形态、凋亡和集落形成测定法研究了大黄酸的强效增殖抑制和促凋亡作用。STAT3 荧光素酶报告测定法、免疫染色分析和 Western blot 分析揭示了抑制 IL6/STAT3 信号轴。
通过在胰腺癌细胞中联合使用大黄酸和表皮生长因子受体（EGFR）抑制剂，诱导细胞凋亡，这通过细胞凋亡分析和凋亡/抗凋亡蛋白 BCL-2、BAX、Caspase 3 和 Cl-PARP 的表达水平变化得到证实。还观察到联合使用大黄酸和 EGFR 抑制剂后 STAT3 和 EGFR 磷酸化的抑制。最有趣的是，发现大黄酸可显著增强细胞对厄洛替尼的敏感性，从而抑制 PANC-1 和 BxPC-3 异种移植模型中的肿瘤生长。体内抗肿瘤作用与肿瘤残余物中凋亡的增加和 STAT3 和 EGFR 途径的联合抑制有关。
大黄酸通过抑制 STAT3 使人类胰腺癌细胞对 EGFR 抑制剂敏感。综上所述，结果表明大黄酸为胰腺癌治疗提供了新的蓝图，特别是与 EGFR 抑制剂联合使用时。
