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.
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.
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Clare S W
CS
Yan
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Iris L K
IL
Wong
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Kin-Fai
KF
Chan
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Jason W Y
JW
Kan
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Tsz Cheung
TC
Chong
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Man Chun
MC
Law
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Yunzhe
Y
Zhao
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Shun Wan
SW
Chan
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.|Department of Chemistry, McGill University , Montreal, Quebec H3A 2K6, Canada.
Tak Hang
TH
Chan
Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, Hong Kong Polytechnic University , Hong Kong SAR, China.
Larry M C
LM
Chow
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D047309:Flavones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C000610356:FD18 flavonoid dimer; D047309:Flavones; D005419:Flavonoids
P-glycoprotein; dimers; flavonoid; multidrug resistance