The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways

An investigation of the mol. mechanism of the anticancer activity demonstrated by the ruthenium(II)-arene compd. [Ru(η6-p-cymene)Cl2(pta)] (pta is 1,3,5-triaza-7-phosphaadamantane), termed "RAPTA-C", in Ehrlich ascites carcinoma (EAC) bearing mice is described. RAPTA-C exhibits effective cell growth inhibition by triggering G2/M phase arrest and apoptosis in cancer cells. Cell cycle arrest is assocd. with increased levels of p21 and reduced amts. of cyclin E. RAPTA-C treatment also enhances the levels of p53, and its treatment triggers the mitochondrial apoptotic pathway, as shown by the change in Bax to Bcl-2 ratios, resulting in cytochrome c release and caspase-9 activation. c-Jun NH2-terminal kinase (JNK) is a crit. mediator in RAPTA-C-induced cell growth inhibition. Activation of JNK by RAPTA-C increases significantly during apoptosis. Overall, these results suggest a crit. role for JNK and p53 in RAPTA-C-induced G2/M arrest and apoptosis of EAC-bearing mice. Consequently, RAPTA-C treatment results in a significant inhibition in the progression of cancer in an animal model, which emulates the human disease, and does so with remarkably low general toxicity; hence, RAPTA-C has potential for clin. application.