In Vitro and In Vivo Anticancer Activities of Water-Soluble Ru(II)(η6-<i>p</i>-cymene) Complexes via Activating Apoptosis Central Regulators and Possibilities of New Antitumor Strategies in Triple Negative Breast Cancers

In this study, we synthesized 12 monofunctional tridentate ONS-donor salicylaldimine ligand (<b>L</b>)-based Ru(II) complexes with general formula [(Ru(<b>L</b>)(<i>p</i>-cymene)]⁺·Cl^- (<b>C1</b>-<b>C12</b>), characterized by ¹H NMR, ¹³C NMR, UV, FT-IR spectroscopy, HR-ESI mass spectrometry, and single-crystal X-ray analysis showing ligand's orientation around the Ru(II) center. All 12 of these 12 complexes were tested for their anticancer activities in multiple cancer cells. The superior antitumor efficacy of <b>C2</b>, <b>C8</b>, and <b>C11</b> was demonstrated by reduced mitochondrial membrane potential, impaired proliferative capacity, and disrupted redox homeostasis, along with enhanced apoptosis through caspase-3 activation and downregulation of Bcl-2 expression. In the 4T1 breast cancer orthotopic mouse model, assessment of bioluminescence for metastatic spread, tumor burden, histopathological evaluation, immunohistochemistry (IHC), and hematological profiling and tissue Protein expression of caspase-3, cleaved caspase-3, TNF-α, and bcl-2 demonstrated that <b>C8</b> treatment led to prolonged survival and suppressed tumor progression in triple negative breast cancer.