Levistolide A overcomes P-glycoprotein-mediated drug resistance in human breast carcinoma cells.
OBJECTIVE
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-tetrazolium 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.


CONCLUSIONS
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.
Chen
Fei
F
National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China. faithchen@yahoo.com
Wang
Tao
T
Wang
Jia
J
Wang
Zi-qiang
ZQ
Qian
Ming
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D008970:Molecular Weight; D000091402:Prohibitins; D012016:Reference Values; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; C000717331:PHB2 protein, human; D000091402:Prohibitins; C523615:levistolide A; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil