Physicochemical Property And Antitumor Activity Of Curcumin Derivative - FM0807

Introduction: Curcumin (Cur) is extracted from rhizomes of Zingiberacease (ginger family) plants, such as turmeric, zedoary, and curcuma aromatic. It has been tested and shown for antitumor, anti-inflammatory, anti-oxidant and anti gallstone activities, as well as lowing blood lipid content and boosting immunity. Curcumin currently remains to be a hot topic because of its antitumor activity, but its instability, poor solubility in water, rapid metabolism rate and poor bioavailability hinder Cur's clinical utilization. Therefore, how to improve Cur's pharmacokinetic characteristic and antitumor activity becomes the major issues and popular topics. We synthesized a curcumin derivative– FM0807 by modifying cur's chemical structure, and it was demonstrated to be a more effective drug than its parent compound– curcumin by assaying its pharmacokinetic behavior, anti-inflammatory and antitumor activities. This result encouraged us for further study on FM0807 and developing it into a first-line anticancer drug with proprietary intellectual property rights. Purpose: This study was performed to test the physicochemical property and antitumor activity of curcumin derivative– FM0807Methods: (1) Factors influence the stability of FM0807 was tested; (2) Hydrolysis kinetics of FM0807 in Phosphate buffer solution with different pH values was measured by high performance liquid chromatography (HPLC). (3) FM0807 solubility and oil/water partition coefficient were measured by HPLC. (4) MTT assay was used to test the in vitro anticancer activity of FM0807 on different types of cancer cells. (5) Compared the anticancer activity of FM0807 with curcumin by applying them to S180 mice implanted with cancer cells in different routes.(6)Measured the anticancer activity of FM0807 in nude mice implanted with Burkitt's lymphoma CA46 cells. (7) Measured the level of Caspase-3 and C-myc protein expression in FM0807 treated CA46 cells by western blot.Results: (1) FM0807 was tested to be stable in high humidity, slight degrade in high temperature, and unstable when exposed to light (significant decrease in mass was observed at the tenth day). (2) FM0807 was more stable than curcumin in buffer solution with pH value range from 2 to 9. (3) Solubility of FM0807 decreased with increasing pH value of aqueous solution, but increased with increasing temperature. (4) FM0807 was highly lipophilic, which enhanced its bioavailability by crossing the phospholipid cell membrane. (5) FM0807 significantly inhibited the growth of CA46, HELA, SGC7901 and SW1116 cells, and the measured IC50 were 9.20μmol/L, 20.80μmol/L, 22.90μmol/L, 44.73μmol/L respectively. (5) 200 mg·kg-1·d-1 oral and intravenous doses of FM0807 inhibited the fibrosarcoma cell growth in S180 mice by 32% and 56% respectively, which were significantly higher than the inhibitive effect of equimolar curcumin (P<0.05). (6) The inhibitive effect of 200 mg·kg-1·d-1 intravenous does of FM0807 on Burkitt's lymphoma CA46 cell growth in nude mice reached 67%. (7) FM0807 increased the level of Caspase-3 protein expression, but decreased the level of C-myc protein expression in CA46 cells.Conclusion: The experimental result showed that FM0807 was a stable prodrug with superior anticancer activity comparing with its parent compound– curcumin. Thus, FM0807 is a promising curcumin derivative, which has the potential to be a first-line anticancer drug with proprietary intellectual property rights.