Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer

Abstract

Background: Overexpression of Discoidin domain receptor 1(DDR1) is known to enhance the malignancy of breast cancer considerably. This study reports the identification of a potent DDR1 inhibitor, Nilotinib for the treatment of breast cancer. Methods: MTT assay was used to evaluate the inhibitory activity of Nilotinib and meantime we used flow cytometry to evaluate the pro-apoptotic activity of Nilotinib against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by shRNA. The effect of DDR1 or treatment with Nilotinib on cell migration was assayed. The expression of p-DDR1, DDR1, p-ERK1/2, ERK1/2 and E-cadherin，Vimentin, Snail1 were detected by western blot and immuno-fluorescent staining . Results: Nilotinib against MCF-7 (IC 50 =0.403 μM) and MDA-MB-231 (IC 50 =0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respective ly. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of Nilotinib to MCF-7 was reduced. Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.