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.
Highlights
Using three different animal models, a melanoma syngeneic model (B16F10), a glioblastoma xenograft model (A172) and an ovarian cancer xenograft model (A2780), we demonstrated that RDC11 was able to reduce tumor growth by more than 50%, with an efficacy similar to or higher than cisplatin [23]
Based on the encouraging in vitro results provided by this second generation of ruthenium complexes active at the nanomolar range, we investigated their in vivo activity and their mode of action
Using the fluorescent properties of RDC34, we observed that the rate of entry of ruthenium complexes within non-cancerous cells was lower compared to the rate measured within cancer cells
Summary
Targeting redox enzymes involved in the oxidative-to-glycolytic metabolism shift constitutes a promising strategy to selectively target cancer cells without affecting the surrounding healthy tissues, thereby potentially bypassing classical mechanisms of resistance against DNA damage. These pathways include the HIF1/2, mTOR, ER stress and NRF2 mechanisms that contribute to the modification of the expression of transporters This was a critical finding, as TP53 is mutated and inactivated in more than 50% of tumors
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