Circumvention of tumor multidrug resistance by a new annonaceous acetogenin: atemoyacin-B.
OBJECTIVE
To explore the effect of atemoyacin-B (Ate) on overcoming multidrug resistance (MDR).


METHODS
Bullatacin (Bul) was used as a positive control. Cytotoxic effects of Bul and Ate were studied with cell culture of human MDR breast adenocarcinoma cells, MCF-7/Dox and human KBv200 cells, and their parental sensitive cell lines MCF-7 and KB. Cytotoxicity was determined by tetrazolium (MTT) assay. The function of P-glycoprotein (P-gp) was examined by Fura 2-AM assay. Cellular accumulation of doxorubicin (Dox) was determined by fluorescence spectrophotometry. Apoptosis was measured by flow cytometry.


RESULTS
IC50 of Ate for MCF-7/Dox, MCF-7, KBv200, and KB cells were 122, 120, 1.34, and 1.27 nmol.L-1, respectively. IC50 of Bul for MCF-7/Dox, MCF-7, KBv200, and KB cells were 0.60, 0.59, 0.04, and 0.04 nmol.L-1, respectively. The cytotoxicities of Bul and Ate to MDR cells were similar to those to parental sensitive cells. Bul and Ate markedly increased cellular Fura-2 and Dox accumulation in MCF-7/Dox cells, but not in MCF-7 cells. The rates of apoptosis in MDR cells were similar to those in sensitive cells induced by Ate.


CONCLUSIONS
There was no cross-resistance of P-gp positive MCF-7/Dox and KBv200 cell lines to Bul and Ate as compared with their sensitive P-gp negative MCF-7 and KB cell lines. The mechanism of the circumvention of MDR was associated with the decrease of P-gp function and the increase of cellular drug accumulation in MDR cells.
Fu
L W
LW
Cancer Center, Sun Yat-Sen University of Medical Sciences, Guangzhou, China. liwufu1368@hotmail.com
Pan
Q C
QC
Liang
Y J
YJ
Huang
H B
HB
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005233:Fatty Alcohols / Q000494:pharmacology*; D016257:Fura-2 / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D005233:Fatty Alcohols; D005663:Furans; C407886:atemoyacin B; C061022:bullatacin; D004317:Doxorubicin; D015107:4-Butyrolactone; D016257:Fura-2