Anti-Proliferative and Anti-Migration Activity of Arene–Ruthenium(II) Complexes with Azole Therapeutic Agents

Legna Colina-Vegas,Alzir Azevedo Batista,Beatriz Cunha,Katia Oliveira,Maribel Navarro,Marcia Cominetti

doi:10.3390/inorganics6040132

Abstract

The efficacy of organoruthenium complexes containing ergosterol biosynthesis inhibitors (CTZ: clotrimazole, KTZ: ketoconazole and FCZ: fluconazole) against tumor cells, and their interaction with important macro-biomolecules such as human serum albumin and DNA have been investigated here. Our experimental results indicated that these ruthenium(II) complexes present spontaneous electrostatic interactions with albumin, and act as minor groove binders with the DNA. The ability of these Ru(II)–azole complexes to inhibit the proliferation of selected human tumor and non-tumor cell lines was determined by MTT assay. Complexes [RuCl(CTZ)(η6-p-cymene)(PPh3)]PF6 (3) and [RuCl(KTZ)(η6-p-cymene)(PPh3)]PF6 (4) were shown to be between 3- and 40-fold more cytotoxic than the free ligands and the positive control cisplatin. Complex 3 was selected to continue studies on the triple negative breast tumor cell line MDA-MB-231, inducing morphological changes, loss of adhesion, inhibition of colony formation, and migration through Boyden chambers, cell cycle arrest in the sub-G1 phase, and a mechanism of cell death by apoptosis. All these interesting results show the potential of this class of organometallic Ru(II) complexes as an antiproliferative agent.

Highlights

According to the WHO, cancer is a generic term for a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body
We recently reported four organoruthenium complexes incorporated in the coordination sphere in the G1 phase, anti-migration, and anti-invasion properties [18]
These results indicate that cell death in MDA-MB-231 cells induced by compound 3 is mainly caused by apoptosis in a concentration-dependent way, in agreement with what was observed for the investigations of the cell death pathway of clotrimazole ligand, through apoptosis triggered by the displacement of key glycolytic enzymes in breast cancer cell proliferation [41], as well as for other organometallic Ru–CTZ complexes [17]

Summary

Introduction

According to the WHO, cancer is a generic term for a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. There are over 100 different known cancer types that affect humans, causing about 8.2 million deaths, estimated as 13% of all deaths worldwide. One of the principal causes of cancer deaths is the developing of tumor metastasis. Metastasis is defined as the capacity of tumor cells to move from the original tumor to adjacent or distant tissues and spread to other organs [2]. Transition metals, multiple platinum derivatives, have been tested in clinical trials against several types of cancers and cisplatin is one of the most potent chemotherapy drugs approved for clinical practice worldwide. The other two FDA-approved agents are carboplatin and oxaliplatin, while nedaplatin, Inorganics 2018, 6, 132; doi:10.3390/inorganics6040132 www.mdpi.com/journal/inorganics

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