In vitro anticancer activity of novel organometallic gold and ruthenium complexes

Abstract

Background: Cancer is a genetic disorder characterized by an uncontrollable cell growth caused by a malfunction in the genes responsible for controlling the growth and division phases of the cell cycle. The disease can either be hereditary or may develop due to carcinogen exposure. During cancer development, there is an increase in cellular oxidative stress, resulting from an imbalance in the production of reactive oxygen species (ROS) and the cell’s antioxidant defences. This plays a significant role in the development of cancer. Furthermore, normal or programmed cell death (apoptosis) is evaded, resulting in continual cell growth. Over the past century, metal-based drugs have been investigated as therapeutic agents and the platinum drugs cisplatin and carboplatin are the two most widely used metal-based chemotherapeutic agents. In addition to platinum complexes, other metals including ruthenium and gold-based complexes have been shown to have antiproliferative activity against melanoma cells. Methods: This study aimed to investigate the anti-cancer activity of fourteen novel gold and ruthenium metal complexes. The gold complexes were derived from two parent compounds (AE215 and AE207) and our research group previously showed that complex AE215 had anti-HIV activity. Therefore, different complexes were synthesized using the parent complexes as a starting point and these complexes were either glycosylated (G3 and G4) acetylated (G5 and G6), or thiolated (G8 and G8) gold complexes; while the ruthenium complexes were either just the ligand (R1), monometallic (R2), bimetallic trans-(R3) and cis-conformation (R4). Using Cisplatin as a control, the differences in the anticancer activity of these different complexes were investigated and the 50% cytotoxic concentrations (CC50) were obtained by treatments at concentrations ranging from 0.78 to 50 µM on the cancer cell lines. These cancer cell lines were HeLa, HepG2 and U937 cells; and the mammalian Vero cell line was used to determine the selectivity of each complex. The complexes were further investigated for their antioxidant activity using the DPPH and NO assays and the effects of the complexes on the induction of apoptosis was investigated through flow cytometry using propidium iodide and Annexin V at CC50 and twice the CC50. Finally, the drug-likeness of the complexes was determined using Molinspiration to determine if the complexes complied with Lipinski’s rule of five for potential drug candidates. Results: Three of the gold complexes (AE215, G3, and G5) and two of the ruthenium complexes (R2 and R3) were cytotoxic and selective to the HeLa cells where they had CC50< 7 µM and SI> 1. AE215, G3, G5, R2, and R3 were more cytotoxic than cisplatin which had a CC50 of 9.92 µM and SI of 1.03. The gold complex G8 and all four ruthenium complexes were cytotoxic to HepG2 cells with CC50< 9 µM and SI> 1. These complexes were more cytotoxic than cisplatin, which had a CC50 of 26.74 µM and an SI of 0.38 for this HepG2 cell line. Three of the gold complexes (AE 215, G3, and G8) and the ruthenium complex R3 were cytotoxic to U937 cells with CC50< 9 µM and an SI> 1. None of the gold complexes showed DPPH-scavenging ability whereas the ruthenium complexes R2, R3, and R4 had slight DPPH-scavenging activity above 20%. All complexes were able to inhibit NO production, where complexes G5, G6, G8, R2, and R3 were able to decrease NO concentration from 80 µM (untreated cells) to below 40 µM when tested on HeLa cells. Complexes R3 and R4 were able to decrease NO concentration from 97 µM (untreated cells) to just below 30 µM, and this reduction was better than that of Vitamin C which decreased NO concentration to just above 32 µM when tested on HepG2 cells. Complexes R2, R3, and R4 were able to decrease NO production from just above 93 µM (untreated cells) to just above 23 µM at CC50. All of the complexes were able to induce apoptosis. Further investigation on the drug-likeness of the complexes showed that only the two gold complexes (AE215 and AE207) abided to all five of Lipinski’s rules of oral bioavailability. Conclusion: The metal complexes presented herein display the potential of being developed into improved anticancer therapies. The complexes were able to inhibit cancer cell progression when tested on HeLa, U937, and HepG2 cancer cells and were more selective than cisplatin, which is currently available on the market. The complexes not only inhibited cancer cell growth, but complexes like R2, R3, and R4 also had antioxidant activity, showing the added benefits of these complexes. The modifications and different conformations of these complexes showed that some complexes were only active against one cancer cell type, while other complexes showed activity against all the tested cancer cells.