Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Abstract

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)3(dmphen)(ptolICN)]+, where dmphen=2,9‐dimethyl‐1,10‐phenanthroline and ptolICN=para‐tolyl isonitrile, called TRIP. This TRIP‐resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild‐type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP‐resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184‐fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP‐binding cassette transporter P‐glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.

Metal complexes for therapeutic applications

“…Capitalizing on these advantages, a variety of metal-containing compounds have already been clinically approved for a wide range of therapeutic applications. Increasing efforts to not only identify bioactive metal complexes [41] but deeply understand their mechanism of action [87][88][89][90] will be an important next step in their advancement and greater acceptance in the medical community (see Outstanding questions). Further investigation into the therapeutic applications of metal complexes will yield novel compounds with increased potency and selectivity and may even lead to the discovery of entirely new therapeutic strategies.…”

Drug combination study of novel oxorhenium(V) complexes

“…Pharmacological modulators such as VRP, which is a specific blocker of the P-glycoprotein (Pgp) mediated drug efflux, could significantly increase cell line sensitivity. In the present study we investigated the effect of VRP on the action of synthesized oxorhenium(V) complexes with the hydrophobic threephenylphosphine (PPh3) ligands, as VRP is a specific blocker of Pgp, and is also known to interact with calcium channels, potassium channels and adrenergic receptors [40,41]. VRP belongs to the first generation pharmacological inhibitors commonly documented to reverse multidrug resistance (MDR), and increase intracellular accumulation of anticancer drugs.…”

Exploring the Potential of Metallodrugs as Chemotherapeutics for Triple Negative Breast Cancer

“…Other transition metals such as rhenium, manganese, rhodium, iridium, and vanadium have also been evaluated for chemotherapeutic use with promising potential. Rhenium compounds have shown preclinical success in pancreatic, prostate, and ovarian cancers, [158,159] and similar preclinical evaluations are being done in renal cancer with iridium derivatives. [160] A recent review by Falasca and co-workers highlighted rhodium, iridium and rhenium-based anticancer agents, [161] while Inkelewicz-Stepniak and co-workers focused on vanadium compounds in another review.…”