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Abstract

High toxicity acquired resistance and serious side effects, prompting the search for novel compounds for cancer treatment. Recently, a Ruthenium (II) complex [Ru (p-cymene)(L)Cl2] (L = 1,3-bis(4-(tert-butyl)benzyl)-1H-imidazol-3-ium chloride) , which named L-4, has been synthesized and characterized. The purpose of this study was to investigate the effects of L-4 against human esophageal squamous carcinoma (ESCC) cell line EC109. Different methods to determine the apoptotic pathways triggered by L-4 in EC109 cells were investigated by using flow cytometry, Hoechst 33258 staining, Caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and western-blotting techniques. Results showed that a dose- and time-dependent reduction occurred in cell viability after exposure to L-4 in EC109 cells. The flow cytometry analysis showed that L-4 induced cell cycle arrest at G2/M phase in EC109 cells, concomitant to p53 and p21 upregulation and Cyclin D1 down-regulation. L-4 also induced ROS-dependent and mitochondria-mediated apoptosis in EC109 cells by targeting the glutathione reductase, leading to generation of ROS, Ca2+ overloading, increase of Bax/Bcl-2 ratio, loss of MMP, release of cytochrome c into the cytosol, and then activation of Caspase-3/-9. Whereas, ROS scavengers, N-acetyl- L-cysteine, significantly attenuated the effects of L-4 on reduction of cell viabilities, activity of GR, generation of ROS, loss of MMP, the dysfunction of mitochondria and induction of apoptosis. The preliminary results suggest that the Ruthenium (II) complex, L-4, inhibits EC109 cells proliferation via blocking cell cycle progression and inducing ROS-dependent and mitochondria-mediated apoptosis, and deserves further investigation as a new chemotherapeutic strategy for patients with esophageal cancer.

Biography

Email: linjianguo@jsinm.org