Use of Cobalt(III) and Copper(II) Complexes With Thiosemicarbazone Ligands and Berberine Chloride as Anti-Cancer Agents Against Triple Negative Breast Cancer

It is a worrying fact that chemotherapeutic options for treating triple negative breast cancer are limited in nature, including the use of inorganic pharmaceuticals such as cisplatin and its analogues. It has been reported that cisplatin has undesirable side effects when used as a chemotherapeutic drug. As such, there is a need to use non-platinum-containing complexes as chemotherapeutic agents. Based on that issue, it has been reported by our research group and others that cobalt- and copper-containing complexes have shown great potential in anti-cancer properties when compared to cisplatin. In this research project, the cytotoxic effects of the following complexes: [Co(phen)2(MeATSC)](NO3)3•1.5H2O•C2H5OH 1 (where phen = 1,10-phenanthroline and MeATSC = 9-anthraldehyde-N(4)-methylthiosemicarbazone) and [Cu(acetylethTSC)Cl]Cl•0.25C2H5OH 2 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2- yl)ethylidene]hydrazinecarbothioamide) were carried out on cancer MDA-MB-231 VIM RFP and non-cancer MCF-10A cell lines by using the CCK-8 viability assay. Moreover, the cell death mechanisms induced after treatment with the complexes were investigated in cancer cells. From the data acquired via in vitro studies, the IC50 values of complex 1 were 17.59 and 61.26 μM in cancer and non-cancer cells, respectively. The IC50 values of complex 2 were 5.63 and 12.19 μM for cancer and non-cancer cells, respectively. Complex 1 induced cancer cell death via activation of oxidative stress which activated apoptosis and pyroptosis; while complex 2 induced cell cycle arrest in the S phase and DNA cleavage. Furthermore, the copper(II) complex [Cu(chromoneTSC)Cl2]•5H2O•0.0625C2H5OH 3 (where chromneTSC = (E)-N-Ethyl-2-((4-oxo-4H-chromen-3-yl)methylene)- hydrazinecarbothioamide) was synthesized and characterized; then used to carry out in vitro studies in combination with berberine chloride (BBC). The combination treatment significantly inhibited the proliferation of breast cancer cells in a dose- and time-dependent manner with a lower cytotoxic effect on non-cancer cells. The co-treatment group significantly increased the number of cells in G2 phase, indicating the growth arrest of cancer cells. Moreover, the combination group showed induction of both intrinsic and extrinsic apoptotic pathways. The results also showed induction of necroptosis via the activation of RIPK3-MLKL pathway.