Sensitization of ABCB1 overexpressing cells to chemotherapeutic agents by FG020326 via binding to ABCB1 and inhibiting its function.

Abstract

The effectiveness of chemotherapeutic treatment is usually limited by the overexpression of adenosine triphosphate binding cassette (ABC) transporters, which mediate multidrug resistance (MDR) by acting as efflux pumps to remove chemotherapeutic agents from MDR cancer cells. Thus, the inhibition of ABC transporters may represent a promising strategy to reverse MDR. This study was to characterize the actions of FG020326, a newly synthesized triaryl-substituted imidazole derivative, to reverse MDR in vitro and in vivo. FG020326 significantly potentiated the cytotoxicity of paclitaxel, doxorubicin, and vincristine in the ABCB1 (P-glycoprotein, P-gp) overexpressing cells KBv200 and MCF-7/adr, but not in the ABCB1 negative parental cell lines KB and MCF-7. However, FG020326 did not alter the cytotoxicity of the aforementioned drugs in ABCC1 (MRP1), ABCC4 (MRP4), ABCG2 (BCRP) and LRP overexpressing cell lines, KB-CV60, NIH3T3/MRP4-2, S1-M1-80 and SW1573/2R120, respectively. FG020326, following p.o. administration, was present in concentrations sufficient for reversal of MDR in mice. The co-administration of FG020326 with paclitaxel or vincristine significantly enhanced the antitumor activity of these drugs without significantly increasing toxicity in the mice bearing the KBv200 cell xenografts. In addition, FG020326, at concentrations that reversed MDR, did not significantly affect the activity of CYP3A4 or alter the pharmacokinetic profile of paclitaxel after co-administration with paclitaxel. FG020326 produced a significant concentration-dependent displacement of [3H]azidopine and inhibition of efflux of drug from cells. Furthermore, FG020326 was co-localized with ABCB1 in cell membranes. Hence, FG020326 is characterized as a third generation MDR modulator that holds great promise for the treatment of cancer patients with ABCB1-mediated MDR.

• Authors: Chun-ling Dai, Yong-ju Liang, Li-ming Chen, Xu Zhang, Wen-jing Deng, Xiao-dong Su, Zhi Shi, Chung-pu Wu, Charles R Ashby Jr, Shin-ichi Akiyama, Suresh V Ambudkar, Zhe-sheng Chen, Li-wu Fu
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 78 Issue 4 Pg. 355-64 (Aug 15 2009) ISSN: 1873-2968 [Electronic] England
• PMID: 19410561 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Acrylates
• Antineoplastic Agents
• Imidazoles
• Multidrug Resistance-Associated Proteins
• methyl 3-(4-(4,5-bis(4-(isopropyl(methyl)amino)phenyl)-1H-imidazol-2-yl)phenyl)acrylate
• Vincristine
• Doxorubicin
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• ATP-Binding Cassette Transporters
• Acrylates (blood, pharmacokinetics, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Disease Models, Animal
• Doxorubicin (pharmacokinetics, pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects, physiology)
• Drug Screening Assays, Antitumor (methods)
• Humans
• Imidazoles (blood, pharmacokinetics, therapeutic use)
• KB Cells
• Mice
• Mice, Nude
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Paclitaxel (pharmacokinetics, pharmacology)
• Vincristine
• Xenograft Model Antitumor Assays