Antitumor effectiveness and mechanism of action of Ru(II)/amino acid/diphosphine complexes in the peritoneal carcinomatosis progression

Abstract

Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF(1) and the [Ru(l-Trp)(bipy)(dppb)]PF(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.

Dual-Action Ru(II) Complexes with Bulky π-Expansive Ligands: Phototoxicity without DNA Intercalation

“…Although many Ru­(II) complexes have shown promising activity in cancer cell lines, few investigations have probed the time scale or mechanism by which these complexes cause cell death. − With the exception of two complexes derived from nonsteroidal anti-inflammatory drugs that showed an approximately equal amount of apoptosis and necrosis, most Ru­(II) complexes induce apoptosis as the dominant mechanism of cell death. Data with 1 and 9 show that early, photoactivated cell death is achieved in both triple-negative breast and prostate cancer cell lines.…”

Ru(II) Compounds: Next-Generation Anticancer Metallotherapeutics?

“…Many researchers are now seeking to develop new mechanisms of cell death by affecting the general molecular framework by these ruthenium therapeutics. ,− The ruthenium therapeutics are most potent when they induce apoptosis by blocking transcription. After the early discovery of ruthenium compounds Clarke has reported a mechanism of the ruthenium compounds by “activation by reduction”.…”