Platinum complexes inhibit HER-2 enriched and triple-negative breast cancer cells metabolism to suppress growth, stemness and migration by targeting PKM/LDHA and CCND1/BCL2/ATG3 signaling pathways

Abstract

Triple-negative-breast cancer (TNBC) and HER-2 enriched positive aggressive types of breast cancer and are highly metastatic in nature. Anticancer agents those target TNBC and HER-2 enriched positive breast cancers are considered important in the field of breast cancer research. In search of the effective anticancer agents, we synthesized Pt(II) complexes to target these cancers. Platinum complexes (C1-C8) were prepared in single step by the reaction of commercially available K₂PtCl₄ with the readily prepared ligands (L1-L8). All these compounds were characterized successfully by different spectroscopic and spectrophotometric analyses. Structures of C1, C3 and C8 were characterized by single crystal X-ray analysis that confirmed the exact chelation mode of the SNO-triply coordinated ligand. All these complexes inhibited the in vitro growth of MCF-7 (luminal-like), MDA-MB-231 (TNBC) and SKBR3 (HER-2 enriched) breast cancer cells. C1, C3 and C7 induced cell death and suppressed the clonogenic potential of these cancer cells. Importantly, C1, C3 and C7 showed potentials to suppress cancer stem cells/mammosphere formation and cell migration ability of MDA-MB-231 and SKBR3 breast cancer cells. These complexes also induced cellular senescence in MDA-MB-231 and SKBR3 cells, thus suggesting a cell retardation mechanism. Similarly, these complexes induced DNA damage by activating p-H2AX expression and promoted autophagy via ATG3/LC3B axis activation in MDA-MB-231 and SKBR3 cells. Furthermore, these complexes decreased the expression of oncogenic proteins such as BCL2 and cylin-D1 those are involved in cancer cell survival and cell cycle progression. To further gain insight, we found that C1 and C7 targeted glycolytic pathways by regulating PKM and LDHA expression, which are involved in glycolysis. Moreover, C1 and C7 suppressed the formation of ATP production that is required for cancer cell growth. Taken together, the easy synthesis and biological assays results point towards the importance of these complexes in MDA-MB-231 (TNBC) and SKBR3 (HER-2 enriched) breast cancer cells by targeting multiple signaling pathways those are considered important during breast cancer progression. This study produces bases for further deeper in vitro or in vivo study that could lead to the effective breast cancer agents which we are working on.

Keywords: Anticancer study; Breast cancer; Cancer cell migration; Cells stemness; Platinum complexes.