Attilio Di Pietro
BMSSI UMR5086 CNRS-University of Lyon, Institute of Protein Biology and Chemistry, Passage du Vercors 7, 69367 Lyon, France
Multidrug ABC (“ATP-binding cassette”) transporters are involved, upon overexpression, in chemoresistant tumors by pumping anticancer drugs out of the cells. For early discovered ABCB1/ “P-glycoprotein”, third-generation drug-efflux inhibitors are under clinical development. For more recently identified ABCG2/“breast cancer resistance protein”, we have screened different series of flavonoids and derivatives, such as flavones, rotenoids and acridones, and more recently chalcones [1, 2], chromones [3, 4], and indenoindoles [5], as inhibitors of mitoxantrone efflux from transfected HEK293 human cells and chemosensitizers of cell proliferation, to establish 3D-Quantitative Structure-Activity Relationships. Two types of selective, non-competitive, inhibitors have been characterized, either inhibiting or stimulating the basal ATPase activity. The most potent one is indeed efficient in vivo on SCID mice, xenografted with human ABCG2-transfected cells, by chemosensitizing tumor growth to the drug-substrate irinotecan [6]. These selective inhibitors constitute good drug candidates, with low intrinsic toxicity, as sensitizers of cell proliferation to conventional chemotherapeutics.
The “Multidrug Resistance Protein 1” ABCC1 is able to catalyze the efflux of either glutathione conjugates or free glutathione together with hydrophobic substrate drugs. We have identified modulators such as verapamil [7, 8] mimicking substrates and inducing a fast and massive efflux of intracellular glutathione from ABCC1-overexpressing cells, leading to a selective cell death through apoptosis, due to “collateral sensitivity”, or hypersensitivity. The overexpressed transporter then constitutes the Achilles’heel of such resistant cancer cells. Since verapamil is known for its cadiotoxic effects, we investigated other types of modulators such as xanthones, flavones [9] and flavonoid dimers. Glutathione efflux appeared to be necessary, but not sufficient alone, to trigger apoptosis, indicating the contribution of other partner(s) or signaling pathway(s). Such apoptosis inducers may constitute a new type of anticancer drugs operating through an original strategy aimed at selectively targeting and eliminating multidrug-resistant tumors overexpressing the ABCC1 transporter [10].
REFERENCES
[1] Gauthier et al. (2012) J. Med. Chem. 55, 3193.
[2] Winter et al. (2014) J. Med. Chem. 57, 2930.
[3] Valdameri et al. (2012) J. Med. Chem. 55, 966.
[4] Winter et al. (2013) J. Med. Chem. 56, 9849.
[5] Gozzi GJ et al. (2014) J. Med. CheM. 57, in press.
[6] Arnaud et al. (2011) Eur. J. Cancer 47, 640.
[7] Trompier et al. (2004) Cancer Res. 64, 4950.
[8] Perrotton et al. (2007) J. Biol. Chem. 282, 31542.
[9] Lorendeau et al. (2014) Biochem. Pharmacol. 90, 235.
[10] Szakazs et al. (2014) Chem. Rev. 114, 5753.