Identification of Xanthones as Selective Killers of Cancer Cells Overexpressing the ABC Transporter MRP1
0301 basic medicine
0303 health sciences
Xanthones
Antineoplastic Agents
Apoptosis
Transfection
Glutathione
Cell Line
3. Good health
Structure-Activity Relationship
03 medical and health sciences
Verapamil
Cricetinae
Neoplasms
Animals
Humans
Multidrug Resistance-Associated Proteins
DOI:
10.1002/cmdc.201100102
Publication Date:
2011-06-01T13:27:47Z
AUTHORS (8)
ABSTRACT
AbstractMultidrug‐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.
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