Hinokitiol Inhibits Melanogenesis via AKT/mTOR Signaling in B16F10 Mouse Melanoma Cells.

H inokitiol purified from the heartwood of cupressaceous plants has had various biological functions of cell differentiation and growth. Hinokitiol has been demonstrated as having an important role in anti-inflammation and anti-bacteria effect, suggesting that it is potentially useful in therapies for hyperpigmentation. Previously, hinokitiol inhibited the production of melanin by inhibiting tyrosinase activity. The autophagic signaling pathway can induce hypopigmentation. This study is warranted to investigate the mechanism of hinokitiol-induced hypopigmentation through autophagy in B16F10 melanoma cells. The melanin contents and expression of microthphalmia associated transcription factor (MITF) and tyrosinase were inhibited by treatment with hinokitiol. Moreover, the phosphorylation of the protein express levels of phospho-protein kinase B (P-AKT) and phospho-mammalian targets of rapamycin (P-mTOR) were reduced after hinokitiol treatment. In addition, the microtubule associated protein 1 light chain 3 (LC3) -II and beclin 1 (autophagic markers) were increased after the B16F10 cell was treated with hinokitiol. Meanwhile, hinokitiol decreased cellular melanin contents in a dose-dependent manner. These findings establish that hinokitiol inhibited melanogenesis through the AKT/mTOR signaling pathway.

Salmonella-Mediated Cytolethal Distending Toxin Transfer Inhibits Tumor Growth.

The Salmonella enterica serovar Choleraesuis (S.C.) has potential as an antitumor agent because of its tumor-targeting characteristics. S.C. can also be used for specific delivery of therapeutic agents and continuous release during replication. Previously, we successfully used S.C. as a vector to transfer a therapeutic gene and oncolytic virus, which suggested that modified S.C. is suitable for incorporating other antitumor agents into a single system. Cytolethal distending toxin B (CdtB) produced by Campylobacter jejuni can induce tumor cell apoptosis. Here we coated CdtB with poly(allylamine hydrochloride) (PAH) to yield PAH-CdtB. Treatment of cells with PAH-coated CdtB induced apoptosis, demonstrating that the compound retained antitumor activity. Furthermore, S.C. coated with PAH-CdtB (CdtB-S.C.) maintained tumor-targeting activity and had an enhanced antitumor effect. Measurement of the cytotoxic effect of CdtB-S.C. in vitro in a tumor cell line showed increased apoptosis whereas treatment of tumor-bearing mice with CdtB-S.C. reduced tumor growth and prolonged survival. Taken together, our results provide evidence that Salmonella carrying CdtB could have application for the treatment of tumors.