Experimental chemotherapy against xenografts derived from multidrug resistant KBv200 cells and parental drug-sensitive KB cells in nude mice by annonaceous acetogenin 89-2.
OBJECTIVE
Annonaceous acetogenin 89-2 was obtained from atemoya plant. To investigate the effect of 89-2 on experimental chemotherapy against xenografts derived from multidrug resistant KBv200 cells and parental drug-sensitive KB cells.


METHODS
Cytotoxicity was determined by tetrazolium (MTT) assay. The models of KB and KBv200 xenografts in nude mice were established to investigate the effect of 89-2 on experimental chemotherapy against cancer in vivo. Mechanistic experiments were conducted to examine the function of P-gp by Fura 2-AM assay.


RESULTS
The compound 89-2 showed potent cytotoxicity in KBv200 and KB cells, and the mean IC50 of 89-2 to KBv200 and KB cells was 48.7 and 64.6 nmol.L-1, respectively. The IC50 of 89-2 to multidrug resistant (MDR) cells was similar to that to the parental drug-sensitive cells (P < 0.05). In the models of KBv200 and KB cell xenografts in nude mice, 89-2 (0.90 mg.kg-1, q2d x 6) exhibited 52.3% and 56.5% in inhibiting the growth of xenografts, respectively. The toxicity was endurable. The intracellular accumulation of Fura-2 in KBv200 cells increased to 1.66, 2.03, and 2.74-fold, respectively, by addition of 12.8, 64 and 320 nmol.L-1 of 89-2.


CONCLUSIONS
Both MDR KBv200 cells and parental drug-sensitive KB cells were sensitive to the treatment of 89-2 in vitro and in vivo. The mechanism of overcoming MDR was associated with the decrease of P-gp function MDR cells.
Fu
Li-wu
LW
Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China. Fuliwu@hotmail.com
He
Li-rong
LR
Liang
Yong-ju
YJ
Chen
Li-ming
LM
Xiong
Hui-yu
HY
Yang
Xiao-ping
XP
Pan
Qi-chao
QC
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000494:pharmacology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D031041:Annona / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000627:therapeutic use; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010946:Plants, Medicinal / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
C485237:3-(13-(4-(4-(1,5,6-trihydroxyundecyl)tetrahydrofuran-1-yl)tetrahydrofuran-1-yl)tridecyl)-5-methylfuran-2H,5H-2-one; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D005233:Fatty Alcohols; D015107:4-Butyrolactone