The Stability Of Curcumine Prodrug FM0806 And Its Antitumor Effect In Vitro And In Vivo

Introduction: Curcumin is a natural phenolic compound isolated from turmeric (Curcuma longa L).Laboratory research has demonstrated anti一cancer, anti- inflanlrnatory,anti-HIV,anti-hypercholesterolemic,antioxidant properties of its constituent curcumin.However,due to water insolubility and low bioavailability in vivo,the application of curcumin as a Potential anti-tumor drug has been strongly impeded.In order to improve pharmacokinetics properties,we have designed and synthesized a novel curcumin prodrug FM0806.In the present study we investigated its stability and antitumor effect in vitro and in vivo.Aim: To evaluate the stability and the antitumor effect of curcumine prodrug FM0806 in vitro and in vivo.Methods: (1) The influencing factor experiment studies have analyzed the stability of FM0806;(2) Prodrug hydrolysis in aqueous buffer solutions with pH 2-10 as well as 80% mouce plasma solution by the reversed-phase high performance liquid chromatography ( RP-HPLC) method; (3) The MTT assay was used to examine the proliferation arrest of a variety of tumor cells induced by FM0806 and its metabolites; (4) A HPLC,LC-MS method was established to analyze the parent drug and its metabolites; (5) The H22 and K562 murine xenograft models were established and antitumor effect of FM0806 in vivo was analyzed; (6) The expressions of P210^bcr/abl in tumor tissues were detected by immunohistochemistry staining.Results: (1) FM0806 are relatively stable Under the high temperature, the humidity,the illumination condition; (2) It showed no spontaneous hydrolysis at pH 2-10,but was susceptible to hydrolysis by blood plasma; (3) FM0806 was unable to inhibit remarkably the proliferation of tumor cell lines,but we found that the serum containing metabolites obtained from mice with administration of FM0806 100 mg/kg had significant antiproliferative effects in cancer cells,and decreased the expression of P210^bcr/abl and the related downsream signal proteins; (4) HPLC-MS analysis showed that the T1/2 and the area under curve of Cur in plasma of administration of FM0806 in mice were 10-20 fold higher than those of Cur, respectively; (5) FM0806 showed significant inhibitory effect on H22 xenograft in mice models,the inhibitory rates at dose of 50-100 mg/kg were 40-75 %; (6) FM0806 showed significant inhibitory effect on K562 xenograft in nude mice model,the inhibitoryrate at dose of 60 mg/kg was 66.6 %;(7) The positive expression rates of P210^bcr/abl in tumor tissue in gived FM0806 group were obviously lower than those in control group.Conclusion: FM0806 increases the bioavailability and anticancer activities, suggesting its promise for clinical utility as a Cur prodrug.