Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance

Chow, Mun Juinn; Licona, Cynthia; Pastorin, Giorgia; Mellitzer, Georg; Ang, Wee Han; Gaiddon, Christian

doi:10.1039/c6sc00268d

Cited by 76 publications

(71 citation statements)

References 47 publications

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“…Previous work showed that metal-based compounds containing ruthenium could induce endoplasmic reticulum (ER) stress. [32,33] In addition to apoptosis, ER stress can induce autophagy and caspase-independent cell death. [33] To assess the activity of ER stress, we performed Western blot on ATF4 (activating transcription factor 4) (Figure 9).…”

Section: Resultsmentioning

confidence: 99%

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Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

et al. 2017

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Section: Resultsmentioning

confidence: 99%

“…[32,33] In addition to apoptosis, ER stress can induce autophagy and caspase-independent cell death. [33] To assess the activity of ER stress, we performed Western blot on ATF4 (activating transcription factor 4) (Figure 9). Interestingly, 1·PF 6 strongly induced ATF4 in AGS cells, whereas cisplatin had no effect.…”

Section: Resultsmentioning

confidence: 99%

Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

et al. 2017

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“…The authors also found that the water-soluble and stable half-sandwich arene Ru(II) Schiff-base (RAS) complexes, 4f and 4g , can induce non-apoptotic programmed cell death (PCD) through the ER stress pathway. 148 The mechanism of action was significantly different between the two complexes, despite modest structural variations. 4g elicited ROS-mediated ER stress, while 4f ’s efficacy was independent of ROS.…”

Section: Arene Ruthenium(ii) Complexesmentioning

confidence: 97%

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

et al. 2017

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Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. The ruthenium(III) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(II) complexes have also attracted significant attention as anticancer candidates; however, only few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(II) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(II)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(II) complexes, their targeted delivery, and their activity in nanomaterial systems.

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“…The major mechanism of action proposed for these agents is through the production of reactive oxygen species (ROS). Only a few studies have discovered metal complexes that induce ER stress in the absence of ROS generation . The ability of TRIP to induce ER stress independent of ROS generation indicates that it operates via a different mechanism than many other metallodrugs targeting the ER.…”

Section: Figurementioning

confidence: 99%

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

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et al. 2019

Chemistry A European J

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Complexes of the element Re have recently been shown to possess promising anticancer activity through mechanisms of action that are distinct from the conventional metal‐based drug cisplatin. In this study, we report our investigations on the anticancer activity of the complex [Re(CO)3(dmphen)(p‐tol‐ICN)]+ (TRIP) in which dmphen=2,9‐dimethyl‐1,10‐phenanthroline and p‐tol‐ICN=para‐tolyl isonitrile. TRIP was synthesized by literature methods and exhaustively characterized. This compound exhibited potent in vitro anticancer activity in a wide variety of cell lines. Flow cytometry and immunostaining experiments indicated that TRIP induces intrinsic apoptosis. Comprehensive biological mechanistic studies demonstrated that this compound triggers the accumulation of misfolded proteins, which causes endoplasmic reticulum (ER) stress, the unfolded protein response, and apoptotic cell death. Furthermore, TRIP induced hyperphosphorylation of eIF2α, translation inhibition, mitochondrial fission, and expression of proapoptotic ATF4 and CHOP. These results establish TRIP as a promising anticancer agent based on its potent cytotoxic activity and ability to induce ER stress.

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Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance

Abstract: Varying the arene ligand on organoruthenium compounds induced the differential activation of ER stress pathways, leading to non-apoptotic programmed cell death and bypassing drug resistance mechanisms.

Cited by 76 publications

References 47 publications

Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

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

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