| Backgrounds and ObjectiveHepatocellular carcinoma (HCC) is the fifth most common disease in the world and the third major cause of cancer-related deaths. The incidence of this tumor type ranges from approximately 10 cases per 100 000 in North America and Western Europe to 50-150 per 100 000 in Asia and Africa. Despite improvement in liver surgery,patient prognoses after surgical resection for hepatocellular carcinoma(HCC) remain unsatisfied.One of the obstacles in managing post-operative recurrence is multidrug resistance (MDR) to chemotherapy. Multidrug resistance (MDR) is a phenomenon encountered in cancer treatments in which the tumors become resistant to a variety of cytotoxic chemotherapeutic agents. The molecular basis for one major type of MDR is the overexpression of the P-glycoprotein (P-gp), a plasma membrane glycoprotein with molecular masses ranging from 130 to 170 kDa, confering resistance to a broad range of commonly used chemotherapeutic drugs and other hydrophobic agents. Anticancer agents, such as anthracycline derivatives including adriamycin(ADR),cis-dichlorodiamineplatinum (CDDP), and 5-fluorouracil (5-FU), have been used for these treatments. HCC, however, is often resistant to these drugs. The key for succeeding in chemotherapy against HCC is highly dependent on how we can control drug resistance. Cepharanthin hydrochloride (CH), is a natural bisbenzy- lisoquinoline alkaloid extracted from the roots of Stephania cepharantha and salificatied with Hydrochloric Acid. Recently, cepharanthine has been reported to potentiate the activity of some anticancer agents including ADR and to restore the effect of anticancer drugs in multidrug resistant cancer cells.It is, therefore, fascinating to consider the potential benefit of CH when treating HCC mice and the study demenstrates the positive effect of Ch in overcoming MDR by inhibiting the drug efflux through p-gp.Materials and MethodsDrug sensitivity testing with [3-(4,5-dimethylthi-azol-2-yl)-2,5 diphenyl-terazolium bromide] MTT assay showed that CH significantly enhanced cytotoxicity of adriamycin(ADR), cis-dichlorodiamineplatinum (CDDP),and 5-flurouracil(5-FU), but only in resistant cells, while,using the ATP-hydrolisis,we showed that compared with VER,CH increased ATPase activity approximately with a Km of 1.11mg/kg and Vmax of 184nmol/(min-mg).Life-prolongation test showed that CH combined with ADR,CDDP,5-FU significantly prolong the survival time of the mice.Results1,Cell toxicity test showed the small toxicity of CH and VER on BALB/c mice is 1.0mg/ml and 0.15mg/ml respectively;2,Statistical analysis with the MTT method showed resistance index (RI) of H22/FAP tumor cells (RI(H22/ADR)=27.75,RI(H22/CDDP)=10.20,RI (H22/5-FU)=11.20), and it supported powerfully that a HCC multidrug resistance model was established successfully. IC50 of H22/ADR cells (≈3.33) increased by 26.75 fold vs the group of H22 cells (≈0.12), respectively with H22/CDDP cells increased by 9.20 fold and H22/5-FU increased by 10.20 fold.3,CH10mg/kg,CH5mg/kg,VER1.25mg/kg in combination with FAP prolonged the life of BALB/c mice with the life prolongation rate about 40.1%,48.8%,39.8% (P<0.05,vs FAP group);4,In vivo, CH increased ATPase activity approximately with a Km of 1.11mg/kg and Vmax of 184nmol/(min·mg).Conclusions1,The data showed CH combined with FAP agents prolonged the life of mice significantly.2,One of the mechanism is that CH combined with FAP can increase the activity of P-gp ATPase. |
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