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Disrupting lung tumor growth via histone deacetylases (HDACs) inhibition is a strategy for cancer therapy or prevention. Targeting HDAC6 may disturb the maturation of heat shock protein 90 (Hsp90) mediated cell cycle regulation. In this study, we demonstrated the effects of semisynthesized NBM-T-BBX-OS01 (TBBX) from osthole on HDAC6-mediated growth arrest in lung cancer cells. The results exhibited that the anti-proliferative activity of TBBX in numerous lung cancer cells was more potent than suberoylanilide hydroxamic acid (SAHA), a clinically approved pan-HDAC inhibitor, and the growth inhibitory effect has been mediated through G1 growth arrest. Furthermore, the protein levels of cyclin D1, CDK2 and CDK4 were reduced while cyclin E and CDK inhibitor, p21Waf1/Cip1, were up-regulated in TBBX-treated H1299 cells. The results also displayed that TBBX inhibited HDAC6 activity via down-regulation HDAC6 protein expression. TBBX induced Hsp90 hyper-acetylation and led to the disruption of cyclin D1/Hsp90 and CDK4/Hsp90 association following the degradation of cyclin D1 and CDK4 proteins through proteasome. Ectopic expression of HDAC6 rescued TBBX-induced G1 arrest in H1299 cells. Conclusively, the data suggested that TBBX induced G1 growth arrest may mediate HDAC6-caused Hsp90 hyper-acetylation and consequently increased the degradation of cyclin D1 and CDK4.

NBM-T-L-BMX-OS01 (BMX) was derived from the semisynthesis of osthole, isolated fromCnidium monnieri(L.) Cuss., and was identified to be a potent inhibitor of HDAC8. This study shows that HDAC8 is highly expressed in the pancreas and the brain. The function of HDAC8 in the brain has not been adequately studied. Because BMX enhances neurite outgrowth and cAMP response element-binding protein (CREB) activation, the effect of BMX on neural plasticity such as learning and memory is examined. To examine declarative and nondeclarative memory, a water maze, a passive one-way avoidance task, and a novel object recognition task were performed. Results from the water maze revealed that BMX and suberoylanilide-hydroxamic-acid-(SAHA-) treated rats showed shorter escape latency in finding the hidden platform. The BMX-treated animals spent more time in the target quadrant in the probe trial performance. An analysis of the passive one-way avoidance results showed that the BMX-treated animals stayed longer in the illuminated chamber by 1 day and 7 days after footshock. The novel object recognition task revealed that the BMX-treated animals showed a marked increase in the time spent exploring novel objects. Furthermore, BMX ameliorates scopolamine-(Sco-) induced learning and memory impairment in animals, indicating a novel role of BMX in learning and memory.

Royal jelly (RJ) is a widely used natural food. It is also a major source of nutrition for queen bees and plays a key role in their development. RJ is secreted from the hypopharyngeal and mandibular glands of young adult worker bees. The regulation of gene expression in these two glands may influence the development of queen bees by affecting the content of RJ. This study investigated the epigenetic effects in these two glands in young adult worker bees treated with histone deacetylase inhibitors (HDACis), a U.S. Food and Drug Administration-approved drug, suberoylanilide hydroxamic acid (SAHA), and NBM-HD-1, a novel compound synthesized in this laboratory. Western blot analyses indicated that the levels of acetyl-histone 3 and p21 protein expression in MCF-7 cells increased markedly after treatment with NBM-HD-1. The data proved that NBM-HD-1 was a novel and potent HDACi. Furthermore, a method of affecting epigenetic regulation of the mrjp family gene in the hypopharyngeal and mandibular glands of young adult worker bees was developed by feeding young adult worker bees HDACi. Epigenetic regulation produced several important biological effects. A marked change in the protein composition of the RJ secreted from these treated bees was found. Only the ratio of specific major royal jelly protein 3 (MRJP3) was significantly altered in the treated bees versus the untreated controls. Other MRJP family proteins did not change. This alteration in the ratio of royal jelly proteins resulted in a significant increase in the body size of queen bee larvae. The data seem to suggest that HDACis may play an important role in the epigenetic regulation of the hypopharyngeal and mandibular glands of young adult worker bees. They appear to change mrjp3 gene expression and alter the ratio of MRJP3 protein in RJ. This study presents the first evidence that HDACis are capable of regulating the ratio of MRJP3 proteins in RJ, which has the potential to change the body size of queen bees during their development.

Ethnopharmacological relevance Taiwanese green propolis (TGP) extract contains a variety of chemical components and has proven to have broad-spectrum biological activities, including anticancer, antioxidant, and antimicrobial activities. Propolin G, an active anticancer component of TGP, was isolated and characterized in this study. Histone deacetylase inhibitors (HDACis) have been shown to be effective anticancer agents. The aim of this study was to develop a novel HDACi and investigate its anticancer mechanism. Materials and methods NBM-HD-3, a novel HDACi, was derived from propolin G. Two brain cancer cell lines (c6 and DBTRG-05MG) were used in the anti-proliferation assay. NBM-HD-3 treated cells were analyzed by flow cytometry in the cell cycle assay. The gene expression of NBM-HD-3 treated cells was determined by real-time quantitative PCR. HDAC enzyme assay, confocal microscopy and Western blot assay were used to validate NMB-HD-3 as HDACi. Western blot assay was used for analyzing cell cycle modulation by PTEN and AKT. Results NBM-HD-3 was found to have potent anti-proliferative activity in brain cancer cells (rat C6 glioma and human DBTRG-05MG glioblastoma). Western blot analysis and HDAC enzyme assay indicated that NBM-HD-3 was an HDAC inhibitor. The Western blot data exhibited increased levels of p21, Ac-histone 3, Ac-histone 4, and Ac-tubulin after brain cancer cells being treated with NBM-HD-3. NBM-HD-3 also affected the cell cycle regulators such as p21 and cyclin B1. In the study for its anticancer mechanism, NBM-HD-3 was found to increase PTEN and AKT protein levels significantly, while decreasing p-PTEN and p-AKT levels markedly. Conclusion This study demonstrated that the novel compound, NBM-HD-3, is a potent HDAC inhibitor. It produces anticancer activity through modulation of PTEN and AKT in brain cancer cells.