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

Introduction

Peritoneal carcinomatosis is a locoregional cancer widespread within the peritoneal cavity and may occur as result of metastatic primary lesion from the stomach, ovary, intestine, colorectal, and, less commonly, lung and breast. It is considered potentially lethal clinical condition.^1–3 Usually, progression of the disease is associated with formation malignant ascites that causes abdominal pain and pressure, bloating, fatigue, nausea, and anorexia.^4,5

The therapeutic options for peritoneal carcinomatosis are limited because complete surgical removal is not possible and systemic chemotherapy is not effective due to low concentration within the peritoneal cavity.⁶ However, currently the treatment options have improved significantly. Intraperitoneal chemotherapy was introduced in treatments of peritoneal carcinomatosis to increase drug levels locally.⁷

Thus, metallodrugs are being developed to help overcome the limitations of the efficacy and safety of current cancer therapies.^8,9 In recent years, ruthenium complexes have attracted much attention as new transition-metal-based antitumor agents, as they have certain advantages over the platinum complexes that are currently used in cancer chemotherapy.¹⁰ They show less toxicity, they are selective of tumor cells, and present a novel mechanism of action, the prospect of non-cross-resistance and a different spectrum of activity.^11–19

In a previous study, we recently reported that complexes with the general formula [Ru(AA-H)(dppb)(bipy)]PF₆ (AA-H = amino acid anion) inhibited the growth of Ehrlich carcinoma cells in vitro.²⁰ Among the Ru(II)/amino acid/diphosphine complexes evaluated, those with l-methionine and l-tryptophan present the best activity against Ehrlich carcinoma cells, with IC₅₀ values (concentration that results in a 50% reduction in cellular viability) of 10.2 ± 2.3 µM and 8.7 ± 3.1 µM, respectively.²⁰

Ehrlich carcinoma is a murine mammary adenocarcinoma, referred to as an undifferentiated carcinoma, has high transplantable capability, no-regression, rapid proliferation, shorter life span, and 100% malignancy.^21,22 The ascitic form of the tumor is widely used as an experimental model for new chemotherapeutic studies. Ehrlich ascites carcinoma (EAC) is considered similar to the human tumors which are the most sensitive to chemotherapy due to its undifferentiated feature and rapid proliferation rate.^22,23

Thus, the aim this study was to analyze the antitumor efficacy and side effects of the [Ru(l-Met)(bipy)(dppb)]PF₆ (1) and the [Ru(L-Trp)(bipy)(dppb)]PF₆ (2) complexes (Figure 1) using the cisplatin as a...