MDR reversal activity of bromotetrandrine in vitro and in vivo.
The present study was aimed to evaluate the MDR reversal activity of bromotetrandrine (BrTet) in vitro and in vivo. The inhibitory effects of adriamycin (ADM) used alone or in combination with BrTet or Tet on the proliferation of K562 and K562/A02 cells were evaluated by MTT assay. The ADM accumulation and the protein levels of P-glycoprotein (P-gp) were detected by flow cytometry. The mRNA levels of P-gp were determined by RT-PCR. The in vivo effect of BrTet and Tet was investigated by using nude mice grafted with sensitive human leukemia cell line K562 and MDR cell line K562/A02. The results showed that BrTet at 0.25, 0.5 and 1 micromol/L reversed the resistance to ADM in MDR K562/A02 cells in a dose-dependent manner. Flow cytometry suggested that BrTet significantly increased the intracellular accumulation of ADM in K562/A02 cells in a dose-dependent manner. BrTet also inhibited the overexpression of P-gp in K562/A02 cells, and down-regulated mdr1 expression. In nude mice bearing K562 xenografts on the left flank and K562/A02 xenografts on the right flank, intraperitoneal injection of 10 mg/kg BrTet significantly enhanced the antitumor activity of ADM against K562/A02 xenografts with inhibitory rates of 26.1%, while ADM alone inhibited the growth of K562/A02 xenografts only by 5.8%. No enhancement effect by BrTet was seen in K562 xenografts. It is concluded that BrTet shows significant MDR reversal activity in vitro and in vivo. Its activity may be related to the inhibition of P-gp overexpression and the increase intracellular accumulation of anticancer drugs. BrTet may be a promising-MDR modulator for eventual assessment in the clinic.
Cheng
Jian
J
Department of Hematology, Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing 210009, Jiangsu Province, China.
Wang
Jue-Qiong
JQ
Chen
Bao-An
BA
Gao
Feng
F
Xu
Wen-Lin
WL
Shen
Hui-Lin
HL
Ding
Jia-Hua
JH
Gao
Chong
C
Sun
Yun-Yu
YY
Wang
Jun
J
Zhao
Gang
G
Song
Hui-Hui
HH
Bao
Wen
W
Sun
Qian
Q
Dai
Yong-Yuan
YY
Sun
Xin-Chen
XC
Cheng
Hong-Yan
HY
Deng
Yu-Xia
YX
Li
Guo-Hong
GH
Chen
Ning-Na
NN
Liu
Li-Jie
LJ
Wang
Xue-Mei
XM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044182:Benzylisoquinolines; C514835:bromotetrandrine