Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), a leading cause of cancer mortality worldwide. Hepatitis B X protein (HBx) and pre-S2 mutant have been proposed as the two most important HBV oncoproteins that play key roles in HCC pathogenesis. Curcumin is a botanical constituent displaying potent anti-inflammatory and anti-cancer properties without toxic side effects. Phytosomal formulation of curcumin has been shown to exhibit enhanced bioavailability, improved pharmacokinetics, and excellent efficacy against many human diseases. However, effectiveness of phytosomal curcumin for HCC treatment remains to be clarified. In this study, we evaluated chemopreventive effect of phytosomal curcumin on HBV-related HCC by using a transgenic mouse model specifically expressing both HBx and pre-S2 mutant in liver. Compared with unformulated curcumin, phytosomal curcumin exhibited significantly greater effects on suppression of HCC formation, improvement of liver histopathology, decrease of lipid accumulation and leukocyte infiltration, and reduction of total tumor volume in transgenic mice. Moreover, phytosomal curcumin exerted considerably stronger effects on activation of anti-inflammatory PPARγ as well as inhibition of pro-inflammatory NF-κB than unformulated curcumin. Furthermore, phytosomal curcumin showed a comparable effect on suppression of oncogenic mTOR activation to unformulated curcumin. Our data demonstrated that phytosomal curcumin has promise for HCC chemoprevention in patients with chronic HBV infection.
Highlights
Two hepatitis B virus (HBV) viral proteins, the hepatitis B X protein (HBx) and pre-S2 mutant large hepatitis B surface antigen (HBsAg), have been well demonstrated as oncoproteins that exhibit either direct or indirect oncogenic effects in the liver of chronic HBV carriers, contributing to the progression of HCC15,16
Curcumin has been shown to exert its anti-inflammatory effects through activating peroxisome proliferator-activated receptor γ (PPARγ) that results in inhibition of pro-inflammatory nuclear factor-κB (NF-κB) activation[27,28] as well as anti-cancer effects through blocking the oncogenic mammalian target of rapamycin (mTOR) signal activation[29]
The transgenic mice were generated in the C57BL/6 background and the HBx and pre-S2 mutant transgenes were driven by the liver-specific albumin promoter (Fig. 1A)
Summary
Two HBV viral proteins, the hepatitis B X protein (HBx) and pre-S2 mutant large hepatitis B surface antigen (HBsAg), have been well demonstrated as oncoproteins that exhibit either direct or indirect oncogenic effects in the liver of chronic HBV carriers, contributing to the progression of HCC15,16. Hepatocytes co-expressing HBx and pre-S2 mutant exhibit enhanced activation of the oncogenic mammalian target of rapamycin (mTOR) signal pathways induced by either HBx or pre-S2 mutant alone[23] Transgenic mice harboring both HBx and pre-S2 mutant display consistently activated mTOR signal throughout the liver tumorigenesis and have significantly higher frequency and shorter time to develop HCC than mice carrying either viral protein alone[23]. In this study, we evaluated the chemopreventive effect of phytosomal curcumin on HBV-related HCC development by using the transgenic mouse model expressing both HBx and pre-S2 mutant. The inhibitory effect of phytosomal curcumin on the activation of pro-inflammatory and oncogenic signals was determined and compared with the unformulated curcumin
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
