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Nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) is a major transcription factor which regulates many biological and pathological processes such as inflammation and cell proliferation, which are major implicates in cancer progression. [6]-Shogaol ([6]-SHO) is a major constituent of ginger, exhibits various biological properties such as anti-oxidants, anti-inflammation and anti-tumor. Recently, we proven that [6]-SHO prevents oral squamous cell carcinoma by activating proapoptotic factors in in vitro and in vivo experimental model. However, the preventive efficacy of [6]-SHO in 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis (HBP) has not been fully elucidated, so far. Hence, we aimed to investigate the effect of [6]-SHO on inflammation and cell proliferation by inhibiting the translocation of NF-κB and AP-1 in DMBA induced HBP carcinogenesis. In this study, we observed upregulation of inflammatory markers (COX-2, iNOS, TNF-α, interleukin-1 and -6), cell proliferative markers (Cyclin D1, PCNA and Ki-67) and aberrant activation of NF-κB, AP-1, IKKβ, c-jun, c-fos and decreased IκB-α in DMBA induced hamsters. Conversely, oral administration of [6]-SHO strongly inhibited constitutive phosphorylation and degradation of IκB and inhibit phosphorylation of c-jun, c-fos, resulting in inhibition of nuclear translocation of NF-κBp65 and AP-1. Thus, inhibition of NF-κB and AP-1 activation by [6]-SHO attenuates inflammation and cell proliferative response in DMBA induced hamsters. Our finding suggested that [6]-SHO is a novel functional agent capable of preventing DMBA induced inflammation and cell proliferation associated tumorigenesis by modulating multiple signalling molecules., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Diosmin is naturally found flavanoid in many citrus fruits known to have anti-inflammatory, antihyperglycemic, antioxidant and antimutagenic properties. Effects of Diosmin on IL-6/STAT-3 expression in hamster buccal pouch carcinogenesis remain unclear. Alterations in many genes encode crucial proteins, which regulate cell proliferation, differentiation and apoptosis have been implicated in oral cancer. In the present study, we investigated the effect of dietary Diosmin on IL-6/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis by examining the protein expression of IL-6/STAT-3 and its related genes. Immunoblotting and immunohistochemical analyses revealed that Diosmin (100mg/kgb.w) supplement inhibits key events in signaling especially STAT-3 phosphorylation and subsequent nuclear translocation. Results revealed that inhibition of proliferation and angiogenesis is associated with regulation of the STAT-3 pathway; where Diosmin prevents phosphorylation of JAK-1 which was ascend by IL-6, thereby inhibiting STAT-3 phosphorylation. Consequently, an imbalance in the Bax/Bcl-2 ratio triggered the caspase cascade in favor of apoptosis. Transmission electron microscopic studies proved the effect of Diosmin on ultrastructural changes. Finally our results provide significant evidence that Diosmin prevents the development and progression of HBP carcinomas through the inhibition of IL-6/STAT-3 signaling and its downstream events. Thus, Diosmin functions as a potent inhibitor of tumor development and progression by targeting IL-6/STAT-3 signaling may be an ideal candidate for cancer chemoprevention., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)