A New Class of Safe, Potent, and Specific P-gp Modulator: Flavonoid Dimer FD18 Reverses P-gp-Mediated Multidrug Resistance in Human Breast Xenograft in Vivo
Autor: | Yunzhe Zhao, Man Chun Law, Tsz Cheung Chong, Kin-Fai Chan, Larry M.C. Chow, Shun Wan Chan, Tak Hang Chan, Jason W. Y. Kan, Clare S. W. Yan, Iris L. K. Wong |
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Rok vydání: | 2015 |
Předmět: |
Daunorubicin
Blotting Western Pharmaceutical Science Antineoplastic Agents Breast Neoplasms Pharmacology Rhodamine 123 Mice chemistry.chemical_compound Pharmacokinetics In vivo Cell Line Tumor Drug Discovery medicine Animals Humans Doxorubicin ATP Binding Cassette Transporter Subfamily B Member 1 Flavonoids Mice Inbred BALB C business.industry Flavones Drug Resistance Multiple Vinblastine Paclitaxel chemistry Drug Resistance Neoplasm Toxicity Molecular Medicine Female business Neoplasm Transplantation medicine.drug |
Zdroj: | Molecular Pharmaceutics. 12:3507-3517 |
ISSN: | 1543-8392 1543-8384 |
Popis: | Flavonoid dimer FD18 is a new class of dimeric P-gp modulator that can reverse cancer drug resistance. FD18 is a potent (EC50 = 148 nM for paclitaxel), safe (selective index = 574), and selective P-glycoprotein (P-gp) modulator. FD18 can modulate multidrug resistance toward paclitaxel, vinblastine, vincristine, doxorubicin, daunorubicin, and mitoxantrone in human breast cancer LCC6MDR in vitro. FD18 (1 μM) can revert chemosensitivity of LCC6MDR back to parental LCC6 level. FD18 was 11- to 46-fold more potent than verapamil. FD18 (1 μM) can increase accumulation of doxorubicin by 2.7-fold, daunorubicin (2.1-fold), and rhodamine 123 (5.2-fold) in LCC6MDR. FD18 inhibited P-gp-mediated doxorubicin efflux and has no effect on influx. FD18 at 1 μM did not affect the protein expression level of P-gp. Pharmacokinetics studies indicated that intraperitoneal administration of 45 mg/kg FD18 was enough to maintain a plasma level above EC50 (148 nM) for more than 600 min. Toxicity studies with FD18 (90 mg/kg, i.p. for 12 times in 22 days) with paclitaxel (12 mg/kg, i.v. for 12 times in 22 days) revealed no obvious toxicity or death in mice. In vivo efficacy studies indicated that FD18 (45 mg/kg, i.p. for 12 times in 22 days) together with paclitaxel (12 mg/kg, i.v. for 12 times in 22 days) resulted in a 46% reduction in LCC6MDR xenograft volume (n = 11; 648 ± 84 mm(3)) compared to paclitaxel control (n = 8; 1201 ± 118 mm(3)). There were no animal deaths or significant drop in body weight and vital organ wet weight. FD18 can increase paclitaxel accumulation in LCC6MDR xenograft by 1.8- to 2.2-fold. The present study suggests that FD18 represents a new class of safe and potent P-gp modulator in vivo. |
Databáze: | OpenAIRE |
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