8-Prenylnaringenin is an inhibitor of multidrug resistance-associated transporters, P-glycoprotein and MRP1.
Flavonoids with hydrophobic e.g. prenyl substituents might constitute the promising candidates for multidrug resistance (MDR) reversal agents. The interaction of 8-prenylnaringenin (8-isopentenylnaringenin), a potent phytoestrogen isolated from common hop (Humulus lupulus), with two multidrug resistance-associated ABC transporters of cancer cells, P-glycoprotein and MRP1, has been studied for the first time. Functional test based on the transport of fluorescent substrate BCECF revealed that the flavonoid strongly inhibited MRP1 transport activity in human erythrocytes (IC(50)=5.76+/-1.80muM). Expression of MDR-related transporters in drug-sensitive (LoVo) and doxorubicin-resistant (LoVo/Dx) human colon adenocarcinoma cell lines was characterized by RT-PCR and immunochemical methods and elevated expression of P-glycoprotein in resistant cells was found to be the main difference between these two cell lines. By means of flow cytometry it was shown that 8-prenylnaringenin significantly increased the accumulation of rhodamine 123 in LoVo/Dx cells. Doxorubicin accumulation in both LoVo and LoVo/Dx cells observed by confocal microscopy was also altered in the presence of 8-prenylnaringenin. However, the presence of the studied compound did not increase doxorubicin cytotoxicity to LoVo/Dx cells. It was concluded that 8-prenylnaringenin was not able to modulate MDR in human adenocarcinoma cell line in spite of the ability to inhibit both P-glycoprotein and MRP1 activities. To our best knowledge, this is the first report of 8-prenylnaringenin interaction with clinically important ABC transporters.
Wesołowska
Olga
O
Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, 50-368 Wrocław, Poland. olawes@biofiz.am.wroc.p
Wiśniewski
Jerzy
J
Sroda
Kamila
K
Krawczenko
Agnieszka
A
Bielawska-Pohl
Aleksandra
A
Paprocka
Maria
M
Duś
Danuta
D
Michalak
Krystyna
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D027582:Humulus / Q000737:chemistry; D020128:Inhibitory Concentration 50; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048789:Phytoestrogens / Q000302:isolation & purification / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D044950:Flavanones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D048789:Phytoestrogens; C119737:8-prenylnaringenin; C421109:multidrug resistance-associated protein 1