[Correlation between reversing effect of cepharanthine hydrochloride on multidrug resistance and P-glycoprotein expression and function of K562/ADR cells].
In this study, cepharanthine hydrochloride (CH) was tested for its potential ability to modulate the expression and function of P-glycoprotein (P-gp) in the multidrug-resistant human chronic myelogenous leukemia cell line K562/ADR. Cytotoxicity of adriamycin (ADR) alone or in combination with CH or verapamil (VER) in K562 and K562/ADR cells was determined by MTT assay. Based on flow cytometric technology, the effect of CH or VER on the uptake and efflux of rhodamine123 (Rho123) and the accumulation of ADR in these cells was detected by measuring Rho123 or ADR-associated mean fluorescence intensity (MFI). The effects of CH and VER on P-glycoprotein (P-gp) expression in K562 and K562/ADR cells were also measured using a flow cytometry with PE-conjugated P-glycoprotein antibody. The results show that CH significantly enhanced the sensitivity of K562/ADR cells to ADR, 4 micromol x L(-1) of CH enhanced the sensitivity of K562/ADR cells to ADR by 7.43 folds, the reversal activity was 3.19 times higher than that of verapamil. However, CH had no effect on drug-sensitive K562 cells (P < 0.05). CH increased Rho123 and ADR accumulation in a concentration-dependent manner (2-8 micromol x L(-1)) and inhibited the efflux of Rho123 from these cells, but did not affect the accumulation and efflux of Rho123 from the wild-type drug-sensitive K562 cells. The inhibition effect of CH on P-gp expression in K562/ADR cells is in a time- and concentration-dependent manner. The reversal activity of CH is possibility related to inhibition of P-gp function and expression, which lead to an increased intracellular accumulation of anticancer drugs.
Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
You-Mei
YM
Peng
Ning
N
Wang
Ya-Feng
YF
Wang
Li
L
Han
Yan
Y
Zhang
Jin-Hua
JH
Jiang
Yu-Bing
YB
Zhou
Qing-Duan
QD
Wang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D020112:Rhodamine 123 / Q000378:metabolism; D052117:Benzodioxoles
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D004317:Doxorubicin; D020112:Rhodamine 123; C006947:cepharanthine; D052117:Benzodioxoles