Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells.
We investigated the effects of natural flavones, quercetin and morin, and their pentamethyl, pentaethyl, pentapropyl, pentabutyl and pentaallyl ethers, on the function of P-glycoprotein (P-gp) assessed by an increase in the uptake of [3H]vincristine by human myelogenous leukemia (K562) cells and adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Pentamethyl, pentaethyl, pentapropyl and pentaallyl ethers of morin and quercetin (20 microM) all increased the uptake of [3H]vincristine by K562/ADM cells, while quercetin, morin and their pentabutyl ethers had no effect. Pentamethylquercetin, pentaallylquercetin and pentaethylmorin remarkably increased the uptake of [3H]vincristine by K562/ADM cells by 10.6, 10.8 and 14.4-fold, respectively. These inhibitory potencies for P-gp were more potent than typical P-gp inhibitors, cyclosporine A and verapamil. Taking into consideration that these flavonoid derivatives possess antitumor promoter activity, they may become candidates of effective multidrug resistance-reversing agents in cancer chemotherapy.
Ikegawa
Tomomi
T
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Ohtani
Hisakazu
H
Koyabu
Noriko
N
Juichi
Motoharu
M
Iwase
Yukiko
Y
Ito
Chihiro
C
Furukawa
Hiroshi
H
Naito
Mikihiko
M
Tsuruo
Takashi
T
Sawada
Yasufumi
Y
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells / Q000187:drug effects* / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology; D047309:Flavones
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004317:Doxorubicin; D005419:Flavonoids; D011794:Quercetin; D014750:Vincristine; C008548:morin; D047309:Flavones