Abstract
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 G2/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.
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This work was supported by the Foundation of Shanghai Municipal Health Bureau (No 287) and the National High Technology Research and Development Program of China (No 2006AA020501).
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Chen, F., Wang, T., Wang, J. et al. Levistolide A overcomes P-glycoprotein-mediated drug resistance in human breast carcinoma cells. Acta Pharmacol Sin 29, 458–464 (2008). https://doi.org/10.1111/j.1745-7254.2008.00719.x
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DOI: https://doi.org/10.1111/j.1745-7254.2008.00719.x