摘要
Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.
舒尼替尼(sunitinib,SUN)是一种多靶点酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),在使用过程中会由于引发缺氧而增加肿瘤组织中的肿瘤干细胞(cancer stem-like cell,CSC)比例,进而导致肿瘤的耐药和转移。本课题组研究证明,多巴胺(dopamine,DA)可以通过激动多巴胺D1受体(D1 dopamine recpetor,D1DR)抑制耐药性乳腺癌和非小细胞肺癌中的CSC比例进而增强SUN的抗肿瘤药效。本研究考察了DA和SUN联合用药在胰腺癌中的抗肿瘤药效,这是一种具有高致死率,且药物治疗手段极其有限的恶性肿瘤。本研究的细胞毒实验、克隆形成实验和划痕实验结果显示该DA可以显著增强SUN对两种胰腺癌细胞PANC-1、SW1990的细胞生存、克隆形成能力和迁移能力。采用SW1990细胞和胰腺癌患者组织分别构建体内移植瘤模型,发现DA可以显著增强SUN的体内药效,并可被D1DR特异性激动剂SCH23390部分逆转。此外,DA+SUN联合用药组肿瘤中的CSC比例显著低于空白对照组和SUN单药组。动物体重、主要脏器H&E染色和血常规检查结果显示各给药方案安全性良好。综上,DA可显著增强SUN体内外的抗胰腺癌药效,且安全性良好。DA和SUN的联合用药组合具有用于胰腺癌治疗的巨大潜力。
基金
National Natural Science Foundation of China(Grant No.81473277)
Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
