| Kinase Assay: |
| Exp Cell Res. 2015 Mar 15;332(2):236-46. | | Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1α.[Pubmed: 25499970 ] | Gallbladder cancer (GBC) is an aggressive malignancy of the bile duct, which is associated with a low (5-year) survival and poor prognosis. The transcription factor HIF-1α is implicated in the angiogenesis, cell survival, epithelial mesenchymal transition (EMT) and invasiveness of GBC.
METHODS AND RESULTS:
In this study, we have investigated the role of HIF-1α in the pathobilogy of GBC and effect of Hispidulin on the molecular events controlled by this transcription factor. We observed that Hispidulin caused induction of apoptosis, blockade of growth and cell cycle progression in GBC cells. Our results have demonstrated for the first time that Hispidulin-exerted anti-tumor effect involved the suppression of HIF-1α signaling. Hispidulin was found to repress the expression of HIF-1α protein dose-dependently without affecting the HIF-1α mRNA expression. In addition, the inhibition of HIF-1α protein synthesis was revealed to be mediated through the activation of AMPK signaling. Hispidulin also sensitized the tumor cells to Gemcitabine and 5-Fluoroucil by down-regulating HIF-1α/P-gp signaling.
CONCLUSIONS:
Given the low cost and exceedingly safe profile, Hispidulin appears to be a promising and novel chemosensitizer for GBC treatment. | | Cancer Sci., 2011, 102(1):219-25. | | Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2-mediated PI3K/Akt/mTOR signaling pathway.[Pubmed: 21087351] | Hispidulin, an active component from Artemisia vestita, a traditional Tibetan medicinal plant, has been shown to possess anti-inflammatory and anti-oxidative activities. However, the functional role of Hispidulin on tumor growth and angiogenesis has not been elucidated.
METHODS AND RESULTS:
We found that Hispidulin significantly inhibited human pancreatic tumor growth in xenograft mice when s.c. treated at a dosage of 20 mg/kg daily, and this effect was accompanied with a potent inhibition on angiogenesis. When examining the cytotoxicity of Hispidulin on HUVECs and pancreatic cancer cells in vitro, we found that HUVECs were more susceptible to the treatment, suggesting angiogenesis might be the primary target of Hispidulin. Our results further showed that Hispidulin inhibited vascular endothelial growth factor (VEGF)-induced cell migration, invasion, and capillary-like structure formation of HUVECs in a dose-dependent manner. In ex vivo and in vivo angiogenesis assays, we showed that Hispidulin suppressed VEGF-induced microvessel sprouting of rat aortic rings and corneal neovascularization in C57/BL6 mice. To understand the underlying molecular basis, we next examined the effects of Hispidulin on different molecular components in treated HUVECs, and found that Hispidulin suppressed the VEGF-triggered activation of VEGF receptor 2, PI3K, Akt, mTOR, and ribosomal protein S6 kinase, but had little effect on focal adhesion kinase or extracellular signal-regulated kinase at an effective concentration.
CONCLUSIONS:
Taken together, our results indicate that Hispidulin targets the VEGF receptor 2-mediated PI3K/Akt/mTOR signaling pathway in endothelial cells, leading to the suppression of pancreatic tumor growth and angiogenesis. |
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| Structure Identification: |
| J Ethnopharmacol. 2015 May 26;166:18-22. | | Hispidulin, a constituent of Clerodendrum inerme that remitted motor tics, alleviated methamphetamine-induced hyperlocomotion without motor impairment in mice.[Pubmed: 25764963] | Previously, we found a patient with an intractable motor tic disorder that could be ameliorated by the ground leaf juice of Clerodendrum inerme (CI). Furthermore, the ethanol extract of CI leaves effectively ameliorated methamphetamine-induced hyperlocomotion (MIH) in mice, an animal model mimicking the hyper-dopaminergic status of tic disorders/Tourette syndrome, schizophrenia, or obsessive-compulsive disorder. Here, we for the first time identified a constituent able to reduce MIH from the CI ethanol extract that might represent a novel lead for the treatment of such disorders.
METHODS AND RESULTS:
The ethanol extract of CI was sub-divided into n-hexane, dichloromethane, n-butanol and water fractions. Using MIH alleviation as a bioassay, active compounds were identified in these fractions using silica gel chromatography, recrystallization and proton NMR spectroscopy. The dichloromethane and n-hexane fractions were active in the bioassay. Further subfractionation and re-crystallization resulted in an active compound that was identified to be Hispidulin by proton NMR spectroscopy. Hispidulin significantly alleviated MIH in mice at doses that did not affect their spontaneous locomotor activity or performance in the rotarod test, a measure for motor coordination.
CONCLUSIONS:
Hispidulin is a flavonoid that has been isolated from several plants and reported to have anti-oxidative, anti-inflammatory and anti-cancer activities. Here, we for the very first time found that Hispidulin can also alleviate MIH at doses that did not impair motor activity, suggesting a therapeutic potential of Hispidulin in hyper-dopaminergic disorders. |
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