A set of structurally related Ru(η(5)-C5H5) complexes with bidentate N,N'-heteroaromatic
ligands have been evaluated as prospective metallodrugs, with focus on exploring the uptake and cell death mechanisms and potential cellular targets. We have extended these studies to examine the potential of these complexes to target
cancer cell metabolism, the energetic-related phenotype of
cancer cells. The observations that these complexes can enter cells, probably facilitated by binding to plasma
transferrin, and can be retained preferentially at the membranes prompted us to explore possible membrane targets involved in
cancer cell metabolism. Most malignant
tumors present the Warburg effect, which consists in increasing glycolytic rates with production of
lactate, even in the presence of
oxygen. The reliance of glycolytic
cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer
drug development strategies. Considering the interesting findings that some anticancer drugs in clinical use are cytotoxic even without entering cells and can inhibit TPMET activity, we investigated whether redox
enzyme modulation could be a potential mechanism of action of antitumor
ruthenium complexes. The results from this study indicated that
ruthenium complexes can inhibit
lactate production and TPMET activity in a way dependent on the
cancer cell aggressiveness and the concentration of the complex. Combination approaches that target cell metabolism (glycolytic inhibitors) as well as proliferation are needed to successfully cure
cancer. This study supports the potential use of some of these
ruthenium complexes as adjuvants of glycolytic inhibitors in the treatment of aggressive
cancers.