An investigation of the molecular mechanism of the anticancer activity demonstrated by the
ruthenium(II)-arene compound [Ru(eta(6)-
p-cymene)Cl(2)(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 G(2)/M phase arrest and apoptosis in
cancer cells. Cell cycle arrest is associated with increased levels of p21 and reduced amounts 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 NH(2)-terminal
kinase (JNK) is a critical mediator in
RAPTA-C-induced cell growth inhibition. Activation of JNK by
RAPTA-C increases significantly during apoptosis. Overall, these results suggest a critical role for JNK and p53 in
RAPTA-C-induced G(2)/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 clinical application.