Periodic Reporting for period 1 - TSPO METALLODRUGS (Novel, highly effective and selective anticancer metallodrugs)
Reporting period: 2018-02-01 to 2020-01-31
Cancer cells becoming resistant in the course of treatment is a major challenge in cancer chemotherapy. Anticancer agents that target the mitochondria have the potential to bypass resistance mechanisms and to (re )activate cell death pathways that are mutated or lacking in cancer cells. They are also anticipated to act selectively on tumor cells, as these have a deregulated mitochondrial metabolism. TSPO is a relatively small protein located at the outer mitochondrial membrane and is overexpressed in many tumors. It plays a fundamental role in mitochondrial biochemistry and has a regulatory function in mitochondria-mediated cell death pathways. Thioredoxin reductase (TrxR) is a key enzyme for the maintenance of the cellular redox balance and has a mitochondrial isoform. Its inhibition leads to an increase in reactive oxygen species (ROS) and to a decrease in mitochondrial thiols, both events that trigger cell death. The antitumor activity of many gold complexes is due to the ability of gold(I) to inhibit TrxR.
In addition to gold complexes, complexes with Pt(IV) and Cu(II), two other metal ions widely studied in anticancer metalldrug research, were developed and investigated. Two Pt(IV) complexes exhibited IC50 values in breast cancer cells which were 3 - 13 fold lower than that of the reference metallodrug cisplatin and showed selectivity for cancer cells over non-cancerous cells. It was shown for the first time that Pt(IV) pro-drugs for cisplatin with a TSPO binder in an axial position exert cytotoxicity in MCF-7 cells via a multimodal mechanism combining the effects of DNA damage, depolarisation of the mitochondrial membrane potential, swelling and breaking down of the mitochondria and induction of oxidative stress due to enhanced ROS production. Two Cu complexes were synthesized that are more active than the reference metallodrug toward cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines with IC50 values in the low micromolar range (1.4 to 6.0 μM).
It is expected that the work carried out during the project will mainly achieve scientific impact through the generation of new knowledge, as the results of the structure-activity relationship and mechanistic studies can inform further cancer research.