Copper (II) complex of salicylate phenanthroline induces apoptosis of colorectal cancer cells including oxaliplatin-resistant cells

Abstract

Abstract Background: Oxaliplatin is one of the most effective chemotherapy drugs in the treatment of CRC. However, Oxaliplatin resistance still eventually develops, and the drug is associated with serious side effects. In this study, we examined anti-tumor activity and related molecular mechanism of copper (Ⅱ) complex of salicylate phenanthroline [Cu(sal)(phen)] in colorectal cancer (CRC) cells. Methods: Cell viability was determined by MTS assay and cell proliferation was analyzed by colony formation assay. Cell apoptosis was measured by flowcytometry with Annexin V/PI staining. Reactive Oxygen Species and depolarization of mitochondrial membrane potential were measured with ROS kit and JC-1 kit, respectively. The anti-tumor effect of Cu(sal)(phen) in vivo was investigated using the HCT116 cell xenograft model. Results: Cu(sal)(phen) inhibited the growth of colorectal cancer cell lines HCT116 and SW480. Compared to the chemotherapy drug oxaliplatin, Cu(sal)(phen) was more effective at inducing apoptosis, ROS production, and decreased mitochondrial membrane potential in two CRC cell lines HCT116 and SW480. Our western blot showed that the expression of the apoptosis-related proteins Bcl-2 and Survivin as well as upstream regulators p-JAK2 and p-STAT5 were significantly reduced in HCT116 and SW480 after treatment with Cu(sal)(phen). This suggests that Cu(sal)(phen) induces apoptosis of CRC cells via suppressing the JAK2/STAT5 signaling pathway. In vivo, Cu(sal)(phen) inhibited the growth of HCT116 xenografted tumor as compared with the control group. Immunohistochemical results showed that the expression levels of Bcl-2, Survivin, and Ki-67 in tumor tissues were decreased after Cu(sal)(phen) treatment. Conclusions: Cu(sal)(phen) inhibits CRC cells effectively and may have the potential to be developed as a therapeutic drug for CRC