Identification of xanthones as selective killers of cancer cells overexpressing the ABC transporter MRP1

Multidrug‐resistance protein 1 (MRP1) belongs to the ATP‐binding cassette (ABC) transporter family. MRP1 mediates MDR (multidrug resistance) by causing drug efflux either by conjugation to glutathione (GSH) or by co‐transport with free GSH (without covalent bonding between the drug and GSH). We recently reported that the calcium channel blocker verapamil can activate massive GSH efflux in MRP1‐overexpressing cells, leading to cell death through apoptosis. However, clinical use of verapamil is hampered by its cardiotoxicity. Then, in the search for compounds that act similarly to verapamil, but without major side effects, we investigated xanthones. Herein we show that xanthones induce apoptosis among resistant cells overexpressing MRP1 similarly to the verapamil effect. Among the xanthones studied, 1,3‐dihydroxy‐6‐methoxyxanthone was identified as the most active derivative, able to specifically kill cells transfected with human MRP1 with even greater potency than verapamil. Under the same conditions, the active xanthones have no toxic effect on control (sensitive) cells. Xanthones could therefore be considered as new potential anticancer agents for the selective treatment of MRP1‐positive tumors.