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

doi:10.5246/jcps.2020.10.064

Abstract

Abstract:

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.

Key words: Sunitinib, Dopamine, Cancer stem-like cell, Combination therapy, Pancreatic cancer

CLC Number:

R943

Supporting:

Supporting Information

Figure S1. The body weight-time curves of different groups in SW1990 xenograft model (A) and PDX model (B). n = 5, mean±SD.

Figure S2. The hemogram analysis of blood samples from SW1990 tumor-bearing mice of control, DA 2 mg/kg, SUN 40 mg/kg, DA 2 mg/kg + SUN 40 mg/kg groups (mean±SD, n = 5). WBC, white blood cell; GRN, granulocytes; PLT, platelet; PCT, plateletcrit; RDW, red blood cell volume distributing width; MCHC, mean corpuscular hemoglobin concentration; MCH, mean corpuscular hematocrit; MCV, mean corpuscular volume; HCT, hematocrit; HGB, hemoglobin; RBC, red blood cell.

Figure S3. The H&E staining results of main organs including heart, liver, spleen, lung and kidney from SW1990 tumor-bearing mice of control, DA 2 mg/kg, SUN 40 mg/kg, DA 2 mg/kg + SUN 40 mg/kg groups.

Junsheng Xue, Siyuan Wang, Fangran Hao, Xiuyun Tian, Hong Su, Liang Yang, Qiming An, Chunyi Hao, Tianyan Zhou. Dopamine increases the anti-cancer efficacy of sunitinib in the treatment of pancreatic cancer[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(10): 689-700.

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