stilbenes and bakuchiol

Bakuchiol is a promising anti-tumor candidate with resveratrol-like structure. The present study aims to evaluate the inhibition potential of bakuchiol towards UDP-glucuronosyltransferases (UGT) 1A isoforms. An in vitro incubation system using 4-methylumbelliferone (4-MU) glucuronidation was used to evaluate the inhibition capability of bakuchiol towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9 and 1A10. The glucuronidation of trifluoperazine (TFP) was employed as the probe reaction to determine bakuchiol's inhibition towards UGT1A4. At 1 microM and 10 microM of bakuchiol, no or weak inhibition was observed for all the tested UGT1A isoforms. At 100 microM of bakuchiol, the activity of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9 and 1A10 was inhibited by -46.2%, 74.7%, 17.8%, 98.7%, 70.4%, 99.2%, 75.8%, and 93.3%, respectively. Further inhibition kinetic behaviour was determined for UGT1A6, 1A8, and 1A10. Both Dixon plot and Lineweaver-Burk plot showed the noncompetitive inhibition of bakuchiol towards all these three UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 5.3, 1.8, and 92.6 microM for UGT1A6, 1A8, and 1A10, respectively. In combination with the in vivo exposure of bakuchiol, the high possibility of in vivo inhibition of UGT1A6 and 1A8 was predicted. However, relatively low possibility of in vivo inhibition towards UGT1A10 was predicted due to lower in vivo concentration of bakuchiol than its inhibition parameter (Ki). All these information will be helpful for the R&D of bakuchiol as a promising anti-tumor drug.

Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucuronosyltransferase; Humans; Indicators and Reagents; Isoenzymes; Kinetics; Phenols; Resveratrol; Stilbenes

Anti-tumor activity of bakuchiol, an analogue of resveratrol, was investigated on human lung adenocarcinoma A549 cell line. MTT assay revealed that IC(50) of bakuchiol at 72h was 9.58+/-1.12 micromol/l, much lower than that of resveratrol (33.02+/-2.35 micromol/l). Bakuchiol but not resveratrol elevated intracellular reactive oxygen species. Bakuchiol reduced mitochondrial membrane potential (Psim) of cells in a concentration- and time-dependent manner, showing a more potent effect than that of resveratrol. More apoptotic cells were induced by bakuchiol, compared with resveratrol. Subsequently, S phase arrest, caspase 9/3 activaton, p53 and Bax up-regulation, as well as Bcl-2 down-regulation were observed in bakuchiol-treated A549 cells. The results point toward that S phase-related cell cycle regulation, more importantly reactive oxygen species-related apoptosis might contribute to the anticancer properties of bakuchiol, which will strongly support the further development of bakuchiol against non-small-cell lung cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Line; Cell Line, Tumor; Cell Survival; Cells, Cultured; Humans; Inhibitory Concentration 50; Lung Neoplasms; Membrane Potential, Mitochondrial; Mice; Osmolar Concentration; Phenols; Reactive Oxygen Species; Resveratrol; S Phase; Stilbenes; Time Factors; Tumor Suppressor Protein p53