The anti-tumor efficacy and mechanism of C17 in pancreatic cancer: inhibition of cancer stem-like cells

C17 is a small molecule containing 2,4-diaminoquinazoline and aryl piperazine. Docking was used to compare the affinity of C17 for five dopamine receptor (DR) subtypes. Pancreatic cancer SW1990 and PANC-1 cell lines were used in in vitro and in vivo studies. The effect of C17 on the expression level of D1DR was investigated by immunofluorescence. A cytotoxicity assay, clone formation assay and flow cytometry were used to investigate the ability of C17 to inhibit on cell survival, clone formation, and to suppress cancer stem-like cells (CSCs). The ability to suppress tumorigenesis was investigated by inoculating nude mice with SW1990 cells pre-treated with different concentrations of C17. Finally, the anti-tumor efficacy and safety of C17 and its combination with the multitarget tyrosine kinase inhibitor sunitinib (SUN) were evaluated in SW1990 xenograft mice. Our results demonstrate that C17 is most likely to bind to D1DR among the five DR subtypes. D1DR expression was increased in C17-treated cells, which could be reversed by SCH23390, a D1DR-specific antagonist. The IC₅₀ values of C17 on the survival of SW1990 and PANC-1 cells were 12.56 and 10.56 μmol·L^-1, respectively. C17 could suppress clone formation ability, CSC frequency and in vivo tumorigenesis in a dose-dependent manner. In the SW1990 xenograft model, 50 mg·kg^-1 of C17 could weakly inhibit the tumor growth, and the tumor volume with 50 mg·kg^-1 of C17 in combination with 10 mg·kg^-1 of SUN group was smaller than that in SUN 10 mg·kg^-1, SUN 20 mg·kg^-1 group and gemcitabine (GEM) group. In addition, body weight, blood test, and organ index results showed good safety with all dosing regimens. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Peking University. C17 may be a promising candidate for the treatment of pancreatic cancer.