[Reversal of multidrug resistance of tumor cells by FG020327 and its mechanism].
OBJECTIVE
Over-expression of P-glyco-protein (P-gp) in tumor cells results in multidrug resistance (MDR), and failure of chemotherapy. Combined therapy of MDR-related cytotoxins plus MDR modulators is a promising strategy to overcome clinical MDR. This study was to explore MDR reversal activity of a novel compound FG020327, and its mechanism.


METHODS
MTT assay was used to evaluate MDR reversal activity of FG020327 in 2 P-gp expressing tumor cell lines, KBv200 and MCF-7/ADR. Adriamycin (ADM) accumulation in MCF-7/ADR cells was detected by fluorescence spectrophotometry. The effect of FG020327 on P-gp function was showed by rhodamine 123 (Rh123) accumulation and efflux in KBv200 cells.


RESULTS
FG020327 significantly enhanced sensitivity of MDR cells to anti- tumor drugs. Five mumol/L of FG020327 enhanced sensitivity of KBv200 cells to vincristine (VCR) by 44.9 folds, the reversal activity of which was 3 times that of verapamil (VRP). However, FG020327 had little effect on drug-sensitive MCF-7 cells and KB cells. FG020327 of 2.5, 5, and 10 mumol/L also enhanced ADM accumulation in MCF-7/ADR cells by 2.3, 2.7, and 3.7 folds, respectively, but didn't affect ADM accumulation in MCF-7 cells. FG020327 enhanced Rh123 accumulation in KBv200 cells,but not in KB cells.


CONCLUSIONS
FG020327 is an efficient modulator. The reversal of drug-resistance by FG020327 is probably related to enhanced anti-tumor drug accumulation, and inhibition of P-gp function in MDR tumor cells.
Chen
Li-Ming
LM
Research Department, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, P. R. China.
Li
Yan-Fang
YF
Zhang
Xu
X
Yan
Su-Li
SL
Liang
Yong-Ju
YJ
Fu
Li-Wu
LW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology; D012235:Rhodamines / Q000493:pharmacokinetics; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007093:Imidazoles; D012235:Rhodamines; D014750:Vincristine; D004317:Doxorubicin