A Half-Sandwich Ruthenium(II) (N^N) Complex: Inducing Immunogenic Melanoma Cell Death in Vitro and in Vivo

Abstract

Efficacy of clinical chemotherapeutic agents depends not only on direct cytostatic and cytotoxic effects but also involves in eliciting (re)activation of tumour immune effects. One way to provoke long-lasting antitumour immunity is coined as immunogenic cell death (ICD), exploiting the host immune system against tumour cells as a "second hit". Although metal-based antitumour complexes hold promise as potential chemotherapeutic agents, ruthenium (Ru)-based ICD inducers remain sparse. Herein, we report a half-sandwich complex Ru(II) bearing aryl-bis(imino) acenaphthene chelating ligand with ICD inducing properties for melanoma in vitro and in vivo. Complex Ru(II) displays strong anti-proliferative potency and potential cell migration inhibition against melanoma cell lines. Importantly, complex Ru(II) drives the multiple biochemical hallmarks of ICD in melanoma cells, i. e., the elevated expression of calreticulin (CRT), high mobility group box 1 (HMGB1), Hsp70 and secretion of ATP, followed by the decreased expression of phosphorylation of Stat3. In vivo the inhibition of tumour growth in prophylactic tumour vaccination model further confirms that mice with complex Ru(II)-treated dying cells lead to activate adaptive immune responses and anti-tumour immunity by the activation of ICD in melanoma cells. Mechanisms of action studies show that complex Ru(II)-induced ICD could be associated with mitochondrial damage, ER stress and impairment of metabolic status in melanoma cells. We believe that the half-sandwich complex Ru(II) as an ICD inducer in this work will help to design new half-sandwich Ru-based organometallic complexes with immunomodulatory response in melanoma treatments.

Keywords: half-sandwich Ru(II) complex; immunogenic cell death; melanoma; mitochondrial damage; prophylactic tumor vaccination; ruthenium.