A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells

King, Anna; Marker, Sierra C.; Swanda, Robert V.; Woods, Joshua J.; Qian, Shu‐Bing; Wilson, Justin J.

doi:10.1002/chem.201902223

Cited by 56 publications

(69 citation statements)

References 49 publications

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“…Additionally, resistance pathways can often allude to the underlying mechanism or molecular target of the drug candidate . Our lab has been studying the biological and anticancer activity of rhenium‐based compounds, in part because they are not cross‐resistant with the conventional and widely used platinum‐based drugs . Among the compounds that we have investigated, TRIP (Scheme ) was found to be equally as effective as cisplatin in the A2780 ovarian cancer cell line.…”

Section: Resultsmentioning

confidence: 99%

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

et al. 2020

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“…Since the introductiono fp latinum-based chemotherapeutics for the treatment of cancer, [1] there has been sustained effort toward discovering new anticancer metallodrugs of even greater efficacy and selectivity.Awide range of elements have formed the basis of these investigations,h ighlighted by recent examples of complexes based on Fe II , [2] Ga III , [3] Ag I , [4] Re I , [5] Os II , [6] Ir III [7,8] and Au I . [9] Ru II -based compounds have perhaps been the subjecto ft he mosti ntense focus, with the early compounds NAMI-A [10] and KP1019 [11] then the promising RAPTA [12] and RAED [13] familieso fc ompounds pavingt he way for continued research in this area.…”

Section: Introductionmentioning

confidence: 99%

Homo‐ and Hetero‐dinuclear Arene‐Linked Osmium(II) and Ruthenium(II) Organometallics: Probing the Impact of Metal Variation on Reactivity and Biological Activity

Wilson

Prior

Sandland

et al. 2020

Chemistry A European J

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Dinuclear metallodrugs offer much potential in the development of novel anticancer chemotherapeutics as a result of the distinct interactions possible with bio‐macromolecular targets and the unique biological activity that can result. Herein, we describe the development of isostructural homo‐dinuclear OsII–OsII and hetero‐dinuclear OsII–RuII organometallic complexes formed from linking the arene ligands of [M(η6‐arene)(C2O4)(PTA)] units (M=Os/Ru; PTA=1,3,5‐triaza‐7‐phosphaadamantane). Using these complexes together with the known RuII–RuII analogue, a chromatin‐modifying agent, we probed the impact of varying the metal ions on the structure, reactivity and biological activity of these complexes. The complexes were structurally characterised by X‐ray diffraction experiments, their stability and reactivity were examined by using 1H and 31P NMR spectroscopy, and their biological activity was assessed, alongside that of mononuclear analogues, through MTT assays and cell‐cycle analysis (HT‐29 cell line). The results revealed high antiproliferative activity in each case, with cell‐cycle profiles of the dinuclear complexes found to be similar to that for untreated cells, and similar but distinct profiles for the mononuclear complexes. These results indicate these complexes impact on cell viability predominantly through a non‐DNA‐damaging mechanism of action. The new OsII–OsII and OsII–RuII complexes reported here are further examples of a family of compounds operating via mechanisms of action atypical of the majority of metallodrugs, and which have potential as tools in chromatin research.

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“…Recently, the development of nanoparticles (Yu et al, 2019; Yu, Zhang, Liu, Xu, & Liu, 2018) and nonplatinum metal complexes as diagnostic tools and anticancer drugs has been rapidly widening, such as copper (II) (Fei et al, 2019), palladium (II) (Vojtek, Marques, Ferreira, Mota‐Filipe, & Diniz, 2019), ruthenium (II), and gold (III)‐based complexes (King, Marker, Swanda, & Woods, 2019; Ma, Wu, Cheng, & Lee, 2019). Among them, cobalt complexes containing cobalt–Schiff base (Bajema, Roberts, & Meade, 2019), [Co 2 (CO) 6 ] moiety (Gong et al, 2016), cobalt (III)‐polypyridyl (Abe, Eskandari, & Suntharalingam, 2018), cobalt nanowire (Zhu et al, 2019), and cobalt chloride (H. Y. Wang & Zhang, 2015) have attractive tumor cell inhibiting effects.…”

Section: Introductionmentioning

confidence: 99%

Radiosensitivity enhancement by Co‐NMS‐mediated mitochondrial impairment in glioblastoma

Yang

Zhang

et al. 2020

Journal Cellular Physiology

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We investigated the radiosensitizing effects of Co‐NMS, a derivative of nimesulide based on a cobalt carbonyl complex, on malignant glioma cells. In the zebrafish exposed to Co‐NMS ranging from 5 to 20 μM, cell death and heat shock protein 70 expression in the brain and neurobehavioral performance were evaluated. Our data showed that Co‐NMS at 5 μM did not cause the appreciable neurotoxicity, and thereby was given as a novel radiation sensitizer in further study. In the U251 cells, Co‐NMS combined with irradiation treatment resulted in significant inhibition of cell growth and clonogenic capability as well as remarkable increases of G2/M arrest and apoptotic cell population compared to the irradiation alone treatment. This demonstrated that the Co‐NMS administration exerted a strong potential of sensitizing effect on the irradiated cells. With regard to the tumor radiosensitization of Co‐NMS, it could be primarily attributed to the Co‐NMS‐derived mitochondrial impairment, reflected by the loss of mitochondrial membrane potential, the disruption of mitochondrial fusion and fission balance as well as redox homeostasis. Furthermore, the energy metabolism of the U251 cells was obviously suppressed by cotreatment with Co‐NMS and irradiation through repressing mitochondrial function. Taken together, our findings suggested that Co‐NMS could be a desirable drug to enhance the radiotherapeutic effects in glioblastoma patients.

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A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells

Cited by 56 publications

References 49 publications

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Homo‐ and Hetero‐dinuclear Arene‐Linked Osmium(II) and Ruthenium(II) Organometallics: Probing the Impact of Metal Variation on Reactivity and Biological Activity

Radiosensitivity enhancement by Co‐NMS‐mediated mitochondrial impairment in glioblastoma

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