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

Abstract

Oxaliplatin (Oxa) is one of the most effective chemotherapeutic drugs used in the treatment of colorectal cancer (CRC). However, the use of this drug is associated with severe side-effects and patients eventually develop resistance to Oxa. In recent years, copper complexes have been extensively investigated as substitutes for platinum-based drugs. Therefore, a number of copper complexes have also been developed for cancer therapy, such as copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)]. In the present study, the antitumor activity and the related molecular mechanisms of Cu(sal)(phen) were examined in CRC cells. As compared with the chemotherapeutic drug, Oxa, Cu(sal)(phen) was more effective in inducing apoptosis and reactive oxygen species (ROS) production, and in decreasing mitochondrial membrane potential in the CRC cell lines, HCT116 and SW480. In addition, the expression of the apoptosis-related proteins, Bcl-2 and survivin, and those of the upstream regulators, p-JAK2 and p-STAT5, were significantly decreased in the two cell lines following treatment with Cu(sal)(phen). Furthermore, the efficacy of the complex against CRC was found to be excellent in an animal model. The results of immunohistochemical analysis revealed that the expression levels of Bcl-2, survivin and Ki-67 in tumor tissues were decreased following Cu(sal)(phen) treatment. The antitumor mechanisms underlying Cu(Sal)(phen) treatment were the induction of ROS generation, the inhibition of the JAK2/STAT5 signaling pathway and the downregulation of the expression of anti-apoptotic proteins, such as Bcl-2 and survivin. On the whole, the findings of the present study indicated that Cu(sal)(phen) effectively inhibited the viability and proliferation of HCT116 and SW480 CRC cells; in the future, the authors aim to conduct further experiments in future studies to provide more evidence that supports the development of Cu(sal)(phen) as a therapeutic agent for CRC.

Encapsulation of copper phenanthroline within horse spleen apoferritin: characterisation, cytotoxic activity and ability to retain temozolomide

“…5 and SI-11 † ) and comparable with the reported active concentrations found for other Cu( ii )-phenanthroline complexes against HeLa tumour cells 38 or colorectal cancer cells. 39 This showed that encapsulation of Cu(phen) into HSAFt had a limited effect on the activity profile of the metal complex.…”

Copper in colorectal cancer: From copper‐related mechanisms to clinical cancer therapies

“… 206 , 207 The key molecular mechanisms involve the inhibition of topoisomerase IIa activity 208 and interaction with DNA to induce double‐stranded pDNA cleavage. 209 Additionally, copper‐based complexes also promote cancer cell apoptosis through various mechanisms, 210 , 211 including influencing ROS production, 212 , 213 , 214 , 215 inhibiting the activity of the NF‐κB 215 and JAK2/STAT5 signalling pathway, 216 activating the p53 signalling pathway, 217 , 218 , 219 and activating caspase‐related proteins. 220 Moreover, copper‐based complexes can reverse chemoresistance in CRC treatment, particularly against drugs such as oxaliplatin, cisplatin and doxorubicin.…”