Inhibition of P-glycoprotein mediated multidrug resistance by stemofoline derivatives.

Abstract

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.

• Authors: Sonthaya Umsumarng, Komsak Pintha, Pornsiri Pitchakarn, Kwankamol Sastraruji, Thanapat Sastraruji, Alison T Ung, Araya Jatisatienr, Stephen G Pyne, Pornngarm Limtrakul
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 61 Issue 4 Pg. 399-404 ( 2013) ISSN: 1347-5223 [Electronic] Japan
• PMID: 23358236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Heterocyclic Compounds, 4 or More Rings
• didehydrostemofoline
• stemofoline
• Vinblastine
• Doxorubicin
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Antineoplastic Agents (toxicity)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (toxicity)
• Drug Resistance, Neoplasm (drug effects)
• Heterocyclic Compounds, 4 or More Rings (chemical synthesis, chemistry, toxicity)
• Humans
• K562 Cells
• Paclitaxel (toxicity)
• Vinblastine (toxicity)