An Anticancer Rhenium Tricarbonyl Targets Fe−S Cluster Biogenesis in Ovarian Cancer Cells

Abstract

Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Herein, we describe an improved approach to prioritize candidate protein targets based on a combination of dose‐dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 distinct dose‐dependent targets with concentrations of competitive saturation between 0.1 and 32 μM despite the broad proteotoxic effects of TRIP. Target‐response networks revealed two highly probable targets of which the Fe−S cluster biogenesis factor NUBP2 was competitively saturated by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down‐regulation of Fe−S cluster containing proteins and upregulated ferritin. Fe−S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first‐in‐class modulator of the scaffold protein NUBP2, which disturbs Fe−S cluster biogenesis at sub‐cytotoxic concentrations in ovarian cancer cells.

Comparative Study of Sonodynamic and Photoactivated Cancer Therapies with Re(I)-Tricarbonyl Complexes Comprising Phenanthroline Ligands

“…Adequate intracellular uptake for any cancer therapeutic is essential for in vitro and in vivo anticancer activities. − Henceforth, we examined the cellular uptake of Re2 and Re3 in HeLa cells after 6 h of incubation by measuring in-cell fluorescence from the complexes through flow cytometer analysis. , The flow cytometry data (Figure ) clearly depicted that Re2 and Re3 internalized significantly into the HeLa cells within 6 h of incubation. The significant cellular uptake of the complexes encouraged us to study the cytotoxicity of complexes against HeLa (cervical cancer cell line), MCF-7 (breast cancer cell line) cancer cell line, and normal HEK (human embryonic kidney) cell line in both dark and after light exposure using the MTT assay. − Re1 did not present any significant cytotoxicity against any of the tested cell lines with the presence or absence of light (400–700 nm, 5 J cm –2 ) (Table ). Earlier, the Mascharak group reported that Re1 was also nontoxic against MDA-MB231 cells …”

Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses

“…In recent years, metalloproteomics has emerged as a powerful tool to identify the cellular protein targets of various anticancer metal-based drugs. − Different workflows have been designed, the most advanced ones relying on bioorthogonal probes, combined with protein pull-down, shotgun LC-MS/MS analysis, and database interrogation for protein identification. The first step of this workflow can be performed either with cell lysates − or with live cells . This latter strategy has not only been applied to uncover the main protein targets of inert gold­(III) , and bis-cyclometalated iridium­(III) complexes using photoaffinity probes but also of arsenic trioxide , in cancer cells and cisplatin in yeast using azido derivatives.…”

Neutral rhenium(i) tricarbonyl complexes with sulfur-donor ligands: anti-proliferative activity and cellular localization

“…3,5,7,[11][12][13][14] Importantly, fac-[Re(NN)(CO) 3 L] +/0 complexes are uniquely suitable for multimodal biological imaging, 15 including phosphorescence measurements, infrared and Raman spectroscopic mapping (CuO tag) and X-ray fluorescence microscopy (XFM) mapping of Re and other heavy elements (such as I-substituted ligands). 3,[16][17][18][19][20] Another rapidly developing area is the use of fac-[Re (CO) 3 (L) 3 ] +/0 complexes as potential anti-cancer, [2][3][4]6,[21][22][23] antimicrobial, 3,24 and anti-viral 25 drugs. Both imaging and therapeutic uses of fac-[Re(CO) 3 (L) 3 ] +/0 complexes usually require specialized ligands for selective targeting of biological compartments.…”