The anti-hepatitis drug DDB chemosensitizes multidrug resistant cancer cells <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> by inhibiting P-gp and enhancing apoptosis |
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Authors: | Jing Jin Hua Sun Huailing Wei Gengtao Liu |
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Institution: | (1) Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, P.R. China;(2) Present address: Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3XF, UK |
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Abstract: | Summary
Purpose: DDB (dimethyl-4,4′-dimethoxy-5,6,5′6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate) is a synthetic hepatoprotectant which
has been widely used to treat chronic viral hepatitis B patients in China for more than 20 years. In this study, we evaluated
DDB as a multidrug resistance (MDR) chemosensitizing agent.
Methods: A panel of sensitive and resistant cancer cell lines were treated with various concentration of DDB, and the effect on chemosensitivity
and accumulation of anticancer drugs; promotion of apoptosis and P-glycoprotein (P-gp) expression were determined by MTT (Dimethyl
thiazolyl-2,5-diphenyltetrazolium bromide) assay, fluorospectrometry and flow cytometry respectively. Drug resistance reversal
activity of DDB was also examined in BALB/c nude mice bearing both acquired MDR human nasopharyngeal carcinoma KBv200 and
parental KB xenografts. The effect of DDB on the pharmacokinetics of Dox and hematological toxicity induced by Dox was measured
in ICR and C57/BL mice, respectively.
Results: DDB at nontoxic concentrations of 12.5, 25 and 50 μM partly reversed the resistance to vincristine, doxorubicin, paclitaxel
in acquired MDR breast carcinoma MCF-7/Adr cells, KBv200 and intrinsic MDR human hepatocarcinoma Bel7402 cells, whereas no chemosensitizing effect of DDB was observed in sensitive KB and MCF-7 cells. DDB increased the intracellular
accumulation of doxorubicin and inhibited surface P-gp expression in MCF-7/Adr cells. Furthermore, it was found that DDB promoted
doxorubicin-induced apoptosis of Bel7402 cells through enhanced caspase-3 activation. Co-administration of DDB at 300 and 500 mg/kg orally to nude mice increased
the antitumor activity of vincristine to KBv200 xenografts without a significant increase in toxicity. In contrast, Co-administration
of DDB did not inhibit the growth of KB xenografts. DDB also markedly reduced the decrease of leukocytes in doxorubicin-treated
C57/BL mice. Co-administration of DDB increased Dox concentration in ICR mice bearing S180 sarcoma, but no pharmacokinetical
interaction with Dox was observed.
Conclusion: These results indicate that DDB has MDR reversal activity by inhibiting P-gp and when used in combination with anti-cancer
drugs, it could potentially be used as a clinical treatment for P-gp-mediated MDR cancers. |
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Keywords: | DDB Multidrug resistance P-glycoprotein Apoptosis |
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