Inhibition of P-glycoprotein mediated multidrug resistance by stemofoline derivatives.
Resistance to chemotherapy in cancer patients has been correlated to the overexpression of the ATP-binding cassette (ABC) drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. We examined the multidrug resistance reversing property of stemofoline derivatives in drug-resistance human cervical carcinoma (KB-V1) and human leukemic (K562/Adr) cell lines that overexpress P-gp. Didehydrostemofoline and eleven of its derivatives were synthesized and the cytotoxicity and their effect on doxorubicin, vinblastine and paclitaxel sensitivity in drug resistant (KB-V1 and K562/Adr) and drug sensitive (KB-3-1 and K562) cell lines by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were determined. We found that three out of the twelve stemofoline derivatives including OH-A1, NH-B6 and NH-D6 showed commitment efficiency to increase sensitivity to doxorubicin, vinblastine and paclitaxel in KB-V1 cells and increase sensitivity to doxorubicin, and paclitaxel in K562/Adr cells whereas the effects have not been seen in their parental sensitive cancer cell lines (KB-3-1 and K562). These results indicate that stemofoline derivatives reversed P-gp-mediated multidrug resistance in vitro, and thus could be developed as effective chemosensitizers to treat multidrug-resistant cancers. The molecular mechanism of modulation of P-gp would be further determined.
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Sonthaya
S
Umsumarng
Komsak
K
Pintha
Pornsiri
P
Pitchakarn
Kwankamol
K
Sastraruji
Thanapat
T
Sastraruji
Alison T
AT
Ung
Araya
A
Jatisatienr
Stephen G
SG
Pyne
Pornngarm
P
Limtrakul
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D020014:K562 Cells; D017239:Paclitaxel / Q000633:toxicity; D014747:Vinblastine / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C481859:didehydrostemofoline; C430220:stemofoline; D014747:Vinblastine; D004317:Doxorubicin; D017239:Paclitaxel