Open AccessLevistolide A overcomes P‐glycoprotein‐mediated drug resistance in human breast carcinoma cells 1
Author(s) -
CHEN Fei,
WANG Tao,
WANG Jia,
WANG Ziqiang,
QIAN Ming
Publication year - 2008
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2008.00719.x
Subject(s) - flow cytometry , p glycoprotein , apoptosis , multiple drug resistance , vincristine , microbiology and biotechnology , cell cycle , biology , cell growth , drug resistance , verapamil , pharmacology , cancer research , chemistry , medicine , chemotherapy , biochemistry , cyclophosphamide , genetics , calcium
Aim: The aim of the present study was to investigate the reversing effect of levistolide A (LA) on P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) in human breast carcinoma Bcap37/MDR1 cells. Methods: After chemotherapeutic drugs (adriamycin or vincristine) used alone or in combination with LA, cell proliferation was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐tetrazo‐lium bromide assay and cell cycle distribution by flow cytometry. RT‐PCR was used to detect MDR1 gene transcription and the Western blot assay was used to assess P‐gp expression and the cleavages of poly(ADP‐ribose) polymerase and caspase‐3. Apoptosis was detected by terminal transferase‐mediated dUTP nick end‐labeling assay. Moreover, the P‐gp function was evaluated by the intracellular accumulation of the P‐gp substrate detected by flow cytometry. Results: We found the subcytotoxic doses of LA significantly enhanced adriamycin‐ or vincristine‐induced G 2 /M arrest and apoptosis. These effects were consistent with the ability of LA to inhibit P‐gp function. Moreover, LA dramatically enhanced the verapamil (VER) ability to reverse drug resistance. Conclusion: LA has the potential to be developed as a novel P‐gp modulator. Furthermore, the combination of LA and VER might represent a more sufficient but less toxic anti‐MDR regimen.