Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer

Abstract

Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960’s. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes—as well complexes with other metals (osmium, iron, platinum)—can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.

Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?

“…Examples of transition metal complexes that can trigger non-genotoxic cell death include ruthenium (Ru), iridium (Ir), and osmium (Os) complexes. For instance, Meng et al were the first to show that Ru-based organometallic complexes (e.g., ruthenium-derived Compound 11 is shown in Figure 4A) exert, without activation by light, their cytotoxicity via the induction of the ER stress pathway in glioblastoma and colon cancer cells, despite showing some ability to interact with DNA [2,8,[68][69][70]. Activation of the ER stress effector CHOP was shown to be necessary to induce cytotoxicity.…”

“…via the induction of the ER stress pathway in glioblastoma and colon cancer cells, despite showing some ability to interact with DNA [2,8,[68][69][70]. Activation of the ER stress effector CHOP was shown to be necessary to induce cytotoxicity.…”

“…Despite this broad use, platinum salts have limitations caused by the presence of inherent or induced resistance mechanisms, such as mutations in p53 [1]. However, metal-based compounds have a biological and chemical diversity distinct from that of organic drugs, which drives their attractiveness in the search for new therapeutics with new mechanisms of action for treating cancers [2]. They offer a wide range of oxidation states and variable geometries.…”

Targeting of the intracellular redox balance by metal complexes towards anticancer therapy

“…Adaptations resulting from Nrf2 activation may have beneficial effects under stress conditions through modulation of antioxidant pathways but may also participate in the development of resistance to cancer therapy ( Zhang, 2010 ). Due to their implications in cancer pathogenesis, redox homeostasis and the metabolic switch from glycolysis to oxidative phosphorylation appear as promising targets for cancer therapy ( Gaiddon et al, 2021 ). These pathways include HIF1/2 and NRF2 mechanisms that contribute to the modification of the expression of transporters ( e.g .…”

Conception and Evaluation of Fluorescent Phosphine‐Gold Complexes: From Synthesis to in vivo Investigations

“…[7] .. have been investigated. [8][9][10][11][12][13][14][15][16][17][18][19][20] In our case, we are interested in gold salts. [21][22][23][24] They have been used since ancient times and are still under investigation today.…”