Molecular targets of celastrol derived from Thunder of God Vine: Potential role in the treatment of inflammatory disorders and cancer

Kannaiyan, Radhamani; Shanmugam, Muthu K.; Sethi, Gautam

doi:10.1016/j.canlet.2010.10.025

Cited by 306 publications

(225 citation statements)

References 111 publications

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“…Celastrol has been found to inhibit the proliferation, induce apoptosis, and suppress invasion/migration and angiogenesis in a wide variety of tumor models both in vitro and in vivo (16)(17)(18). The efficacy of celastrol to modulate the expression of various key mediators of tumorigenesis such as proinflammatory cytokines, adhesion molecules, potassium channels, NF-kB, TGF-activated kinase 1 (TAK1), CXCR4, VEGF receptor (VEGFR), STAT3, proteasome, and heat shock response has been reported previously (14,17,(19)(20)(21)(22)(23)(24)(25). However, the potential anticancer effects of celastrol and its mechanism of action(s) have never been investigated before in HCCs, which is one of the most lethal cancers.…”

Section: Introductionmentioning

confidence: 94%

Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

Rajendran

Shanmugam

et al. 2012

Cancer Prevention Research

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145

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Cumulative evidences(s) have established that the constitutive activation of STAT3 plays a pivotal role in the proliferation, survival, metastasis, and angiogenesis and thus can contribute directly to the pathogenesis of hepatocellular carcinoma (HCC). Thus, novel agents that can inhibit STAT3 activation have potential for both prevention and treatment of HCCs. The effect of celastrol on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was investigated. The in vivo effect of celastrol on the growth of human HCC xenograft tumors in athymic nu/nu mice was also examined. We observed that celastrol inhibited both constitutive and inducible STAT3 activation, and the suppression was mediated through the inhibition of activation of upstream kinases c-Src, as well as Janus-activated kinase-1 and -2. Vanadate treatment reversed the celastrol-induced modulation of STAT3, suggesting the involvement of a tyrosine phosphatase. The inhibition of STAT3 activation by celastrol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Celastrol also inhibited the proliferation and induced apoptosis in HCC cells. Finally, when administered intraperitoneally, celastrol inhibited STAT3 activation in tumor tissues and the growth of human HCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that celastrol exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo. Cancer Prev Res; 5(4); 631-43. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 94%

Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

Rajendran

Shanmugam

et al. 2012

Cancer Prevention Research

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145

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“…On the other hand, the triterpene celastrol, a natural compound from a Chinese herbal product, has been studied as an antiproliferative molecule of MM cells. Celastrol has various molecular targets, and its ability to modulate the expression of numerous proteins related to a wide range of cellular activities including pro-inflammatory cytokines, adhesion molecules, proteasome activity, topoisomerase II, potassium channels and heat shock response has been reported (Kannaiyan et al 2011a). Kannaiyan et al (2011b) reported that proliferation of MM cell lines was inhibited by celastrol in correlation with the inhibition of constitutive and induced activation of STAT3.…”

Section: Multiple Myelomamentioning

confidence: 99%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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“…Agents derived from natural sources exert a multitude of effects on chronic inflammation-driven diseases including cancer (8). Recently, much attention has been focused on medicinal plants or herbs as potential sources of new therapeutic anticancer drugs due to their lack of toxic effects, relatively lower cost and enhanced effectiveness (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

The anticancer effect of Huaier (Review)

Song

Zhang

2015

Oncology Reports

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Abstract. Trametes robiniophila Murr. (Huaier) is a sandy beige mushroom found on the trunks of trees and has been widely used in traditional Chinese medicine (TCM) for ~1,600 years. The anticancer effects of Huaier have attracted increasing worldwide interest in recent years. Accumulating evidence suggests that the anticancer mechanism of Huaier may be associated with various biological activities, such as inhibition of cell proliferation, anti-metastasis, interference with tumor angiogenesis and tumor-specific immunomodulatory effect. Animal and experimental studies suggest that Huaier is a promising anticancer agent. Further clinical research is warranted to illustrate the untapped chemopreventive and therapeutic potential of Huaier either alone or in conjunction with existing therapies.

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Molecular targets of celastrol derived from Thunder of God Vine: Potential role in the treatment of inflammatory disorders and cancer

Cited by 306 publications

References 111 publications

Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

The anticancer effect of Huaier (Review)

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