Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling

Abstract

An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-Otetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH 2 -terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK-or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. Cancer Res; 70(5); 1932-40. ©2010 AACR.

Piceatannol inhibits phorbol ester-induced expression of COX-2 and iNOS in HR-1 hairless mouse skin by blocking the activation of NF-κB and AP-1

“…Thus, the inhibitory effect of piceatannol on TPA-induced phosphorylation of ERK1/ 2, p38 MAP kinase, and JNK suggest that the compound targets multiple kinases upstream of NF-jB and AP-1. Pharmacological inhibition of another upstream kinase Akt blunted the DNA binding of NF-jB [10] and AP-1 [13] in TPA-treated mouse skin. However, piceatannol did not alter Akt phosphorylation in mouse skin treated with TPA (data not shown).…”

“…According to our previous studies, topical application of TPA enhances the DNA binding of NF-jB in mouse skin through activation of extracellular signal-regulated kinase (ERK) [7], p38 mitogen-activated protein (MAP) kinase [8], IjB kinases (IKKs) [9], and Akt [10]. On the other hand, TPA-stimulated DNA binding of AP-1 in mouse skin is mediated through the activation of p38 MAP kinase [11], c-Jun-N-terminal kinase (JNK) [12], Akt [13], and IKK [14]. A wide variety of antiinflammatory substances have been shown to interfere with the activation of these kinases and transcription factors, thereby reducing the expression of COX-2 and iNOS [6].…”

Anti-Inflammatory and Anticancer Drugs from Nature

“…AP-1 composed of c-jun and c-Fos subunits is inhibited by curcumin in carcinoma of the endometrium. This factor is also inhibited by resveratrol in mammary epithelial cells stimulated with non-carcinogenic LDCs [73], by diallyl trisulfides [71] and by flavonoid quercetin [74]. The activation of AP-1 leads to inflammation, cell transformation, and immune response.…”

“…Activation of JNK activates the transcription factor AP-1, which is inhibited by diallyl polysulfides from garlic and onion [71]. In addition, the PI3K/Akt pathway is inhibited by psoralidin, a compound isolated from the seeds of Psoralea corylifolia [72].…”

Management ofSitotroga cerealellain stored cereal grains: a review

“…It is essential oil is composed of methyl allyl disulphide and diallyl trisulphide (Shrotriya et al 2010). These compounds can be extracted easily (Yang et al 2012).…”