Reversal of P-gp-mediated multidrug resistance by Bromotetrandrine in vivo is associated with enhanced accumulation of chemotherapeutical drug in tumor tissue.
BACKGROUND
Our previous studies have shown that tetrandrine (Tet) reverses the effect of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) both in vitro and in vivo. 5-Bromotetrandrine (Br-Tet) is a newly synthesized brominated derivative of Tet. In this study, we investigated the MDR reversal activity of Br-Tet in vitro and in vivo and the mechanism involved in this reversal.


METHODS
The ability of Br-Tet to reverse drug resistance in vitro was evaluated by MTT assay in human MDR KBv200 cells and the parental drug-sensitive KB cells. A KBv200 cell xenograft model was established to investigate the MDR reversal activity of Br-Tet in vivo. Doxorubicin (Dox) accumulation in KBv200 and KB cell lines was determined by flow cytometry and Dox accumulation in KBv200 xenografts tissue was examined by spectrofluorometer. The effect of Br-Tet on the expression of P-glycoprotein was detected by flow cytometry and Western blot, respectively.


RESULTS
Br-Tet significantly enhanced the cytotoxicity of Dox, paclitaxel, taxotere, vincristine and epirubicin in KBv200 cells but not in KB cells. Co-administration of 10 mg/kg Br-Tet and 2 mg/kg epirubicin significantly enhanced the antitumor activity of epirubicin without increasing the toxicity. Br-Tet increased the Dox accumulation in the MDR KBv200 cell line and in KBv200 xenograft tissue in a time- and dose-dependent manner. However, it did not reduce the expression of P-gp in KBv200 cells.


CONCLUSIONS
Br-Tet caused a significant reversal of P-gp-mediated MDR, not only in vitro but also in vivo. The MDR reversal activity of Br-Tet in vivo was associated with the enhancement of accumulation of chemotherapeutical drugs in tumor tissue.
Chen
Li-Ming
LM
Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
Liang
Yong-Ju
YJ
Zhang
Xu
X
Su
Xiao-Dong
XD
Dai
Chun-Ling
CL
Wang
Feng-Peng
FP
Yan
Yan-Yan
YY
Tao
Li-Yang
LY
Fu
Li-Wu
LW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015251:Epirubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007624:KB Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D043823:Taxoids; C514835:bromotetrandrine; D000077143:Docetaxel; D015251:Epirubicin; D014750:Vincristine; D004317:Doxorubicin; D017239:Paclitaxel