bisdemethoxycurcumin and Carcinoma--Hepatocellular

Bisdemethoxycurcumin (BDMC), a stable bioactive ingredient in curcuminoids, is associated with various antitumor functions, such as proliferation inhibition, metastasis suppression and apoptosis induction, in many cancer types. However, the mechanism of BDMC in hepatocellular carcinoma (HCC) remains unclear.. We assessed the toxicity and the inhibitory effect of BDMC in the HepG2 cell line by using CCK-8 and colony formation assays. The regulatory effects of BDMC on Akt and MAPK signaling were investigated by Western blotting and immunoprecipitation.. We found that the half-maximum inhibitory concentration (IC50) of BDMC after 48 hrs of treatment was 59.13 μM, and BDMC inhibited proliferation in a time- and dose-dependent manner in HepG2 cells. The inhibitory effect was caused by the inactivation of Akt signaling, but not Erk, Jnk or p38 signaling. In addition, the inactivation of Akt signaling was attributed to the inhibition of ubiquitination mediated by K63-Ub but not K48-Ub. Furthermore, we found that BDMC upregulated the expression of CYLD, leading to Akt deubiquitination and inactivation.. BDMC inhibited HCC cell proliferation, and that this effect was induced by Akt inactivation via CYLD-mediated deubiquitination.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Deubiquitinating Enzyme CYLD; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Liver Neoplasms; Molecular Structure; Proto-Oncogene Proteins c-akt; Structure-Activity Relationship; Tumor Cells, Cultured

Bisdemethoxycurcumin (BDCur) has been found widely in foods such as cheese, butter, etc., and in curry (powder) as a spice. It has been reported to possess anticancer activity. However, its poor absorption limited its application. Natural borneol (NB) has been used as a promoter of drug absorption and widely used in candies, beverages, baked goods, chewing gum and other foods. Thus, we investigated whether NB could potentiate the cellular uptake of BDCur, and elucidated the molecular mechanisms of their combined inhibitory effects on HepG2 cells. Our results demonstrate that NB significantly enhanced the cellular uptake of BDCur. Induction of cell cycle arrest in HepG2 cells by NB and BDCur in combination was evidenced by accumulation of the G2/M cell population. Further investigation on the molecular mechanism showed that NB and BDCur in combination resulted in a significant decrease in the expression level of Cdc2 and cyclin B. Moreover, studies also found that ROS acted as an upstream mediator in NB/BDCur-induced HepG2 cell growth inhibition and led to DNA damage with up-regulation of the expression level of phosphorylated ATM and p53. Our findings suggest that the strategy of using NB and BDCur in combination may have promising potential applications in cancer chemoprevention.

Topics: Absorption, Physiological; Antineoplastic Agents, Phytogenic; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Camphanes; Carcinoma, Hepatocellular; CDC2 Protein Kinase; Curcuma; Curcumin; Cyclin B; Diarylheptanoids; Drug Synergism; Food Additives; G2 Phase; Hep G2 Cells; Humans; Liver Neoplasms; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; Rhizome; Tumor Suppressor Protein p53