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Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide with poor prognosis. Numerous studies have attempted to explore alternative regimens aimed at reducing cancer stem cells (CSCs) without compromising the efficacy of conventional chemoradiotherapy. The present study sought to assess the effect of a natural compound honokiol on the reduction of elevated cancer stemness, metastatic capacity, and chemoresistance of oral carcinoma stem cells (OCSCs). Our results demonstrated that honokiol attenuated the cell survival and self-renewal of OCSCs in a dose-dependent manner. Moreover, honokiol downregulated the expression of 2 selective markers of OCSCs, ALDH1, and CD44, as well as the migration and invasion abilities, indicating its potential to suppress cancer stemness. We showed that honokiol reduced the secretion of IL-6 and phosphorylation of STAT3, and the honokiol-inhibited self-renewal, invasion and colony formation were reversed by administration of IL-6. Most importantly, our data demonstrated that honokiol was able to potentiate the effect of Cisplatin, leading to a lower proportion of OCSCs and the decreased cancer stemness features. Taken together, this study demonstrated the benefits of utilizing honokiol as an adjunct therapy for OSCC treatment., (© 2018 Wiley Periodicals, Inc.)

Oral submucous fibrosis (OSF) is a premalignant disorder in the oral cavity, and areca nut chewing habit has been implicated in the persistent activation of myofibroblasts and the subsequent fibrosis. Therefore, it is critical to ameliorate the excessive activities of myofibroblasts prior to the malignant transformation of OSF. In the current study, we evaluated the cytotoxicity of butylidenephthalide (BP), a major phthalide ingredient of Angelica sinensis, in fibrotic buccal mucosal fibroblasts (fBMFs) as well as various myofibroblast hallmarks, including the phenotypical characteristics and fibrosis-related markers. Our results demonstrated that myofibroblast activities, including collagen gel contraction, migration, invasion and wound healing abilities were inhibited in response to BP. The expression levels of myofibroblast marker, α-smooth muscle actin (α-SMA), fibronectin and type 1 collagen A1 were decreased after exposure of BP. Moreover, we found that the EMT-related markers, Twist, Snail and ZEB1 were all downregulated after BP treatment. Most importantly, our findings demonstrated that BP impeded the binding of Snail to the E-box region in the α-SMA promoter, which may lead to inhibition of the arecoline-induced myofibroblast activities. Collectively, our data indicated that BP reduced numerous myofibroblast features in fBMFs and hindered the binding of Snail to α-SMA, thereby may function as an effective and natural antifibrosis compound., (© 2018 Wiley Periodicals, Inc.)

Oral submucous fibrosis (OSF) is a precancerous condition with symptoms of limited mouth opening and areca nut chewing habit has been implicated in its pathogenesis. Hinokitiol, a natural tropolone derived from Chamacyparis taiwanensis, has been reported to improve oral lichen planus and inhibit various cancer cells. Here, we showed that hinokitiol reduced the myofibroblast activities in fBMFs and prevented the arecoline-induced transdifferentiation. Treatment of hinokitiol dose-dependently downregulated the myofibroblast markers as well as various EMT transcriptional factors. In particular, we identified that Snail was able to bind to the E-box in the α-SMA promoter. Our data suggested that exposure of fBMFs to hinokitiol mitigated the hallmarks of myofibroblasts, while overexpression of Snail eliminated the effect of hinokitiol. These findings revealed that the inhibitory effect of hinokitiol on myofibroblasts was mediated by repression of α-SMA via regulation of Snail and showed the anti-fibrotic potential of hinokitiol in the treatment of OSF., (© 2018 Wiley Periodicals, Inc.)

Oral submucous fibrosis (OSF) has been recognized as one of the oral potentially malignant disorders. Areca nut chewing is implicated in this pathological fibrosis, and it causes chronic inflammation and persistent activation of myofibroblasts. As yet, existing treatments only provide temporary symptomatic relief and there is a lack of an effective intervention to cure OSF. Therefore, development of approaches to ameliorate myofibroblast activities becomes a crucial objective to prevent the malignant progression of OSF. In this study, we examined the inhibitory effect of glabridin, an isoflavane extracted from licorice root, on the myofibroblast characteristics in human fibrotic buccal mucosal fibroblasts (fBMFs). Our results showed that myofibroblast activities, including collagen gel contractility, migration, invasion and wound healing abilities were reduced after exposure of glabridin in a dose-dependent manner. Most importantly, we demonstrated that the arecoline-induced myofiroblast activities were abolished by glabridin treatment. Additionally, the expression of the myofibroblast marker α-smooth muscle actin and other fibrogenic marker, type I collagen, in fBMFs were dose-dependently downregulated. Moreover, we showed that the production of TGF-β was suppressed by glabridin in fBMFs and the protein expression of phospho-Smad2 was decreased as well. In summary, our data suggested that glabridin repressed the myofibroblast features in fBMFs via TGF-β/Smad2 signaling pathway. Glabridin also prevented the arecoline-increased myofibroblast activities, and could serve as a natural anti-fibrosis compound for OSF., (© 2017 Wiley Periodicals, Inc.)

Oral submucous fibrosis (OSF) has been indicated as one of the oral potentially malignant disorders. Epidemiological studies have attributed this pathological fibrosis to the habit of areca nuts chewing, which causes chronic inflammation and persistent activation of myofibroblasts in the oral cavity. Hence, it is crucial to find an effective intervention to ameliorate inflammation in order to prevent the malignant progression of OSF. In this study, we assessed the anti-inflammatory effect of the immunomodulatory protein, GMI, extracted from Ganoderma microsporum on the expression proinflammatory cytokines and the myofibroblast characteristics in human fibrotic buccal mucosal fibroblasts (fBMFs). Our results demonstrated that the expression level of interleukin (IL)-6 and IL-8 were decreased after exposure of GMI and the myofibroblast activities, including collagen gel contraction, migration, invasion, and wound healing abilities were inhibited as well. Furthermore, we confirmed these findings in the arecoline-stimulated BMFs. Consistent with the above findings, the expression of the myofibroblast marker α-smooth muscle actin and other fibrogenic markers, such as type I collagen, fibronectin, and vimentin in fBMFs were all reduced in a dose-dependent manner. Collectively, our data suggested that GMI suppressed the proinflammatory cytokines and myofibroblast features in fBMFs, and could serve as a promising and natural antifibrosis agent., (© 2017 Wiley Periodicals, Inc.)