Abstract
Context and objective: Diplotaxis harra (Forssk.) Boiss. (Brassicaceae) is traditionally used as an antidiabetic, anti-inflammatory or anticancer agent. In these pathologies, the glycogen synthase kinase 3 β (GSK3β) is overactivated and represents an interesting therapeutic target. Several flavonoids can inhibit GSK3β and the purpose of this study was to search for the compounds in Diplotaxis harra which are able to modulate GSK3β.Materials and methods: Methanol extracts from D. harra flowers were prepared and the bio-guided fractionation of their active compounds was performed using inflammatory [protease-activated receptor 2 (PAR2)-stimulated IEC6 cells] and cancer (human Caco-2 cell line) intestinal cells. 50–100 μg/mL of fractions or compounds purified by HPLC were incubated with cells whose inhibited form of GSK3β (Pser9 GSK3β) and survival were analyzed by Western blot at 1 h and colorimetric assay at 24 h, respectively. LC-UV-MS profiles and MS-MS spectra were used for the characterization of extracts and flavonoids-enriched fractions, and the identification of pure flavonoids was achieved by MS and NMR analysis.Results: The methanol extract from D. harra flowers and its flavonoid-enriched fraction inhibit GSK3β in PAR2-stimulated IEC6 cells. GSK3β inhibition by the flavonoid-enriched D. harra fraction was dependent on PKC activation. The flavonoid-enriched D. harra fraction and its purified compound isorhamnetin-3,7-di-O-glucoside induced a 20% decrease of PAR2-stimulated IEC6 and Caco-2 cell survival. Importantly, normal cells (non-stimulated IEC6 cells) were spared by these treatments.Conclusion: This work indicates that flavonoids from D. harra display cytotoxic activity against inflammatory and cancer intestinal cells which could depend on GSK3β inhibition.
Highlights
Inflammatory bowel diseases (IBD) are frequent pathologies that result from the interaction between genetic factors and microbial and environmental cues
The main finding of this study elucidated the anti-inflammatory and anticancer effects of the medicinal plant Diplotaxis harra that could be partially supported by flavonol glycosides through glycogen synthase kinase 3 b (GSK3b) regulation
We found that a flavonoid-enriched fraction of D. harra flowers modulates GSK3b
Summary
Inflammatory bowel diseases (IBD) are frequent pathologies that result from the interaction between genetic factors and microbial and environmental cues. The patients with long-standing IBD, such as ulcerative colitis and Crohn’s disease, have an increased risk of developing colorectal cancer (CRC) (Triantafillidis et al 2009). Even though anti-inflammatory therapies and colonoscopy surveillance have decreased the incidence of colitis-induced CRC, new therapeutic approaches are needed to avoid therapeutic resistance and complications. Diet has been implicated in the development and therapy of IBD (Neuman & Nanau 2012). Diet low in fruits and vegetables leads to an increased risk of developing IBD and CRC (Pan et al 2011). Important phytochemicals of the human diet such as flavonoids and isothiocyanates have chemoprotective effects in a number of animal models of experimental IBD and CRC (Pan et al 2011; Dinkova-Kostova 2012). Dietary consumption of flavonoids has been inversely associated with the risk of CRC (Rossi et al 2010)
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