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.

Therapeutic and Diagnostic Applications of Multimetallic Rhenium(I) Tricarbonyl Complexes

“…[8][9][10][11][12][13][14][15] For instance, our group has described the anticancer activity of a series of tricarbonyl rhenium isonitrile polypyridyl complex (TRIP) complexes. [16][17][18] TRIP kills cancer cells via the induction of endoplasmic reticulum (ER) stress, marking a notable divergence from the well-established DNA-binding mechanism of Pt(II) chemotherapeutics. Moreover, the rich photophysical properties of the Re(CO) 3 core have given rise to promising new photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) agents, owing to their ability to generate singlet oxygen ( 1 O 2 ) and carbon monoxide (CO) upon irradiation.…”

Phosphorescent metal complexes as theranostic anticancer agents: combining imaging and therapy in a single molecule

“…Recently, Wilson's group has made a series of efforts to reveal the SARs, stability and mechanisms of rhenium complexes. 81,[84][85][86][87] The distribution and metabolism of drugs in vivo are very important issues for their potential clinical applications. However, few non-platinum-based metallo-anticancer agents have been studied in this aspect.…”

“…Later, the authors constructed a 52resistant ovarian cancer cell line, and identied two genes (the ATP-binding cassette transporter P-glycoprotein and MT1E encoding metallothioneins) involved in its resistance responses. 85 Targeting cancer metabolism and reversing its metabolic machine have emerged as promising strategies for cancer therapy. Our group designed a series of phosphorescent Re(I) complexes (53-56; Scheme 6) with a highly lipophilic bidentate ligand as mitochondria-targeting theranostic anticancer agents.…”

“…Later, the authors constructed a 52 -resistant ovarian cancer cell line, and identified two genes (the ATP-binding cassette transporter P-glycoprotein and MT1E encoding metallothioneins) involved in its resistance responses. 85 …”

Influence of the Nucleophilic Ligand on the Reactivity of Carbonyl Rhenium(I) Complexes towards Methyl Propiolate: A Computational Chemistry Perspective

“…and neutral or anionic monodentate ligands (e.g., halides, pyridines, aqua, phosphines, alkyls, etc.) are functional molecules with applications in several important areas, such as catalytic reduction of CO 2 [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ], luminescence [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], medicinal chemistry [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], supramolecular chemistry [ 47 ], etc. We reported, among others, the synthesis of the complexes [ReY(CO) 3 (N-N)] (Y = alkoxo [ 48 , 49 ], amido [ 50 , 51 ], hydroxo […”