Reversal of P-gp mediated multidrug resistance in-vitro and in-vivo by FG020318.
Overexpression of P-glycoprotein (P-gp) by tumours results in multidrug resistance (MDR) to structurally and functionally unrelated chemotherapeutic drugs. Combined therapy with MDR-related cytotoxins and MDR modulators is a promising strategy to overcome clinical MDR. This study was performed to explore the MDR reversal activity of a novel compound 2-[4-(2-pyridin-2-yl-vinyl) phenyl]-4,5-bis-(4-N,N-diethylaminophenyl)-1(H)-imidazole (FG020318) in-vitro and in-vivo. Tetrazolium (MTT) assay was used to evaluate the ability of FG020318 to reverse drug resistance in two P-gp-expressing tumour cell lines, KBv200 and MCF-7/adr. Intracellular doxorubicin accumulation was determined by fluorescence spectrophotometry in MCF-7/adr cell line. The effect of FG020318 on P-gp function was demonstrated by rhodamine 123 (Rh123) accumulation in KBv200 cells. KBv200 cell xenograft models were established to study the in-vivo effect of FG020318 on reversing MDR. FG020318 was not cytotoxic by itself against P-gp expressing KBv200 cells and MCF-7/adr cells and their parental drug-sensitive KB cells and MCF-7 cells. FG020318 could significantly increase the sensitivity of MDR cells to antitumour drugs including doxorubicin and vincristine in MCF-7/adr cells and KBv200 cells, respectively. It was much stronger than the positive control verapamil in reversal of MDR. FG020318 also increased the intracellular accumulation of doxorubicin in a concentration-dependent manner in MCF-7/adr cells, but did not affect the accumulation of doxorubicin in drug-sensitive MCF-7 cells. The Rh123 accumulation in resistant KBv200 cells was also increased by the addition of FG020318, but Rh123 accumulation was not affected by FG020318 in drug-sensitive KB cells. FG020318 potentiated the antitumour activity of vincristine to KBv200 xenografts and was an efficacious modulator in-vivo. Our results suggested that FG020318 was a highly potent, efficacious MDR modulator not only in-vitro but also in-vivo. The reversal of drug resistance by FG020318 was probably related to the increased anticancer drug accumulation and its inhibition of P-gp function of MDR tumour cells.
Cancer Center, Sun Yat-Sen University, Guangzhou 510060, PR China.
Li-ming
LM
Chen
Yong-ju
YJ
Liang
Ji-wu
JW
Ruan
Yan
Y
Ding
Xiu-wen
XW
Wang
Zhi
Z
Shi
Lian-Quan
LQ
Gu
Xiao-ping
XP
Yang
Li-wu
LW
Fu
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007624:KB Cells; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D012235:Rhodamines; D014700:Verapamil / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C493221:2-(4-(2-pyridin-2-yl-vinyl) phenyl)-4,5-bis-(4-N,N-diethylaminophenyl)-1(H)-imidazole; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D005456:Fluorescent Dyes; D007093:Imidazoles; D011725:Pyridines; D012235:Rhodamines; D004317:Doxorubicin; D014700:Verapamil