Triggering selective apoptosis of multidrug resistant cancer cells overexpressing ABC transporters – Achilles

The aim is to identify compounds targeting multidrug-resistant cancer cells overexpressing ABC transporters for triggering their apoptosis. These compounds, by difference to classical inhibitors of drug-efflux pumps, produce collateral effects by targeting critical components of the pathophysiological matabolism set up by cancer cells in connection to the activity of overexpressed ABC transporter. Our goal is to target the “Achilles'heel” of multidrug-resistant cancer cells.
The hungarian group of Gergely Szakacs, in collaboration with the NIH of Bethesda in United States, has discovered compounds targeting cancer cells overerexpressing the Pgp (ABCB1/P-glycoprotein) ABC transporter and triggering their apoptosis, by likely altering metal chelation components. In parallel, our group in Lyon has demonstrated that verapamil selectively triggers the apoptosis of other cancer cells, which overexpress MRP1 (ABCC1), by producing a massive efflux of reduced glutathione (GSH) upon binding to the transporter and stimulating its activity. The objective of the present French-Hungarian application is to transversally collaborate for further characterize these two original approaches of eliminating cancer cells, and extend the “Achylles' heel” concept to cancer cells overexpressing ABCG2 (BCRP). This is especially relevant since ABCG2 shares transport substrates with both Pgp, such as camptothecins, and MRP1, such as methotrexate and ... GSH ! Furthermore, ABCG2 is a stem-cell marker, which supports studying its role in cancer stem cells.
We propose to study cytotoxic compounds which are selective for cancer cells overexpressing Pgp, MRP1 or ABCG2, and optimize them in vitro i) by screening with cell-survival and GSH-efflux assays, ii) synthesis of derivatives by medicinal chemistry, and iii) establishment of quantitative structure-activity relationships allowing the construction of a molecular model for designing and synthesizing second-generation compounds with more potency and specificity. Targets identification will allow us to elucidate the molecular and cellular mechanism of action of the compounds in connection to apoptotic signaling. Finally, mice models with xenografted human tumors will allow the evaluation of the in vivo activity, towards reduction of tumor growth, of in vitro-selected compounds, which will hopefully constitute a newclass of anticancer drugs.
The project gathers 4 complementary partner teams: 2 French ones from Lyon (F1, F2), and 2 Hungarian ones from Budapest (H1, H2). Partner 1 (F1) is expert in molecular and cellular biology, biochemistry, medicinal chemistry and biocomputing on ABC transporters, Partner 2 (F2) in cellular signaling and animal experimentation, Partner 3 (H1) in cellular biology related to multidrug ABC transporters, and Partner 4 (H2) is a Biotech company dedicated to establish in vitro cell models and in vivo tumor models.
The 3-year proposed project is divided into 4 Tasks/Workpackages. Task 1 is aimed at identifying specific compounds of ABC transporter-overexpressing cells by in silico screening of chemical libraries, and in vitro cell-based screening assays. Task 2 concerns compound optimization by computer-assisted drug design and medicinal chemistry. Task 3 concerns target identification, and investigation of their molecular interaction with compounds and cellular signaling leading to apoptosis.
Coordination will be managed by A. Di Pietro and G. Szakacs. Potential valorisation concerns short-term use of the newly-identified targets for diagnostic and prognostic biomedical applications, and long-term development of new anticancer drugs of clinical relevance.