Physicochemical, biopharmaceutical and anti-hepatocellular carcinoma properties of curcumin diethyl disuccinate

Abstract

Curcumin ( Cur) has been reported for an anticancer activity by inducing apoptosis. However, the poor oral bioavailability of Cur due to chemical instability limits itself for further development as a chemotherapeutic agent. Previously, a succinate ester prodrug of Cur named as curcumin diethyl disuccinate (CurDD) has been designed and synthesized to enhance chemical stability of Cur. In this study, physicochemical and biopharmaceutical properties as well as in vitro and in vivo anti-hepatocellular carcinoma activities of CurDD were investigated and compared with those of Cur. CurDD could improve the stability of Cur in buffer pH 7.4 and simulated gastrointestinal fluids. The bioavailable fractions ( BF) of CurDD had the significantly higher amount of transported Cur and exerted higher cytotoxicity against HepG2 cells comparing to those of Cur (p<0.05). The BF of CurDD induced apoptosis by increasing and suppressing Bax and Bcl-2 expression, respectively, resulting in the activation of caspase-3 and -9 activities in the higher extent in comparison with Cur. CurDD also exhibited the better anti-hepatocellular carcinoma activity in HepG2-induced tumor mice after oral administration in comparison with Cur (p<0.05) . CurDD inhibited the angiogenesis by decreasing COX-2 expression and suppressing VEGF production. These results suggest that CurDD could improve the oral bioavailability as well as the anti-hepatocellular carcinoma activity of Cur. Therefore, CurDD, as a prodrug of Cur, has a potential to be further developed for the treatment of liver cancer.