Dopamine increases the anti-cancer efficacy of sunitinib in the treatment of pancreatic cancer

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.