Arene Ruthenium Complexes Specifically Inducing Apoptosis in Breast Cancer Cells

Monocationic arene ruthenium complexes (RuL1–RuL4) incorporating phenothiazinyl-hydrazinyl-thiazole ligands (L1–L4) have been synthesized, characterized and evaluated as anticancer agents. Their cytotoxicity, antiproliferative activity and alteration of apoptotic gene expression were studied on three cancer cell lines, a double positive breast cancer cell line MCF-7 and two triple negative breast cancer cell lines Hs578T and MDA-MB-231. All arene ruthenium complexes were able to reduce the viability of the breast cancer cell lines, with the highest cytotoxicities being recorded for the [(p-cymene)RuL3Cl]+ (RuL3) complex on the MCF-7 (IC50 = 0.019 µM) and Hs578T cell lines (IC50 = 0.095 µM). In the double positive MCF-7 breast cancer cells, the complexes [(p-cymene)RuL1Cl]+ (RuL1) and [(p-cymene)RuL2Cl]+ (RuL2) significantly upregulated pro-apoptotic genes including BAK, FAS, NAIP, CASP8, TNF, XIAP and BAD, while downregulating TNFSF10. In the triple negative breast cancer cell line Hs578T, RuL1 reduced TNFSF-10 and significantly upregulated BAK, CASP8, XIAP, FADD and BAD, while complex RuL2 also increased BAK and CASP8 expression, but had limited effects on other genes. The triple negative MDA-MB-231 cancer cells treated with RuL1 upregulated NOD1 and downregulated p53, while RuL2 significantly downregulated p53, XIAP and TNFSF10, with minor changes in other genes. The significant alterations in the expression of key apoptotic genes suggest that such complexes have the potential to target cancer cells.