Celastrol: Molecular targets of Thunder God Vine

Salminen, Antero; Lehtonen, Marko; Paimela, Tuomas; Kaarniranta, Kai

doi:10.1016/j.bbrc.2010.03.050

Cited by 275 publications

(223 citation statements)

References 52 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: 93%

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

147

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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: 93%

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

147

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“…Celastrol was identified to be a pentacyclic triterpenoid, belonging to a small category of natural products of triterpene quinine methides (1,2). Containing electrophilic sites within the rings of quinone methide structure, celastrol is able to form covalent Michael adducts with the nucleophilic thiol groups of cysteine residues (3,4).…”

Section: Introductionmentioning

confidence: 99%

Celastrol suppresses the proliferation of lung adenocarcinoma cells by regulating microRNA-24 and microRNA-181b

Yan

Zhang

et al. 2017

Oncol Lett

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Abstract. Cumulative evidence has indicated that celastrol may suppress cancer growth; however, the underlying mechanism requires further investigation. In the present study, A549 cells were treated with various concentrations of celastrol. Lung cancer cell proliferation was evaluated using an MTT assay and observed under a microscope. Cell apoptosis was detected by Annexin V fluorescein isothiocyanate/propidium iodide double-labeled flow cytometry. The results demonstrated that celastrol suppressed proliferation and induced apoptosis in a dose-independent manner. Celastrol may also decrease the phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) and the B cell lymphoma-2 (Bcl-2)/Bcl-2 associated C protein (Bax) ratio. As microRNA (miR-24 and miR-181b) were predicated to target STAT3, STAT3 activation was inhibited in miR-24-or miR-181b-treated A549 cells compared with the control treatment. The ratio of Bcl-2/Bax was further reduced in miR-24 or miR-181b-treated A549 cells. The results were further confirmed by detecting in another lung adenocarcinoma cell line, LTEP-a-2. In summary, the results of the present study demonstrated that celastrol treatment suppressed the proliferation and induced apoptosis by regulating the expression levels of miR-24 and miR-181b.

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“…In human SH-SY5Y neuronal cells, which are employed as a model system in the present study, it has been demonstrated that celastrol prevents the increase in reactive oxygen species that is observed following exposure to the mitochondrial toxin rotenone (Choi et al 2014). The mechanism of action of celastrol involves activation of HSF1 monomers to a trimerized form that binds to HSEs in the promoter regions of inducible heat shock genes resulting in their upregulation (Westerheide et al 2004;Salminen et al 2010;Sharma et al 2015).…”

Section: Discussionmentioning

confidence: 68%

“…Comparison of celastrol and heat shock to induce neuronal Hsps when paired with arimoclomol Celastrol activates HSF1 monomers to a trimerized form that binds to HSEs in the promoter regions of inducible heat shock genes resulting in their upregulation (Westerheide et al 2004;Salminen et al 2010). Heat shock is the classical activator of HSF1, the master regulator of Hsp induction (Morimoto 1993;Sarge et al 1993).…”

Section: Time Course Of Neuronal Induction Of Hsps After Co-applicatimentioning

confidence: 99%

Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

Deane

Brown

2016

Cell Stress and Chaperones

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Celastrol: Molecular targets of Thunder God Vine

Cited by 275 publications

References 52 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

Celastrol suppresses the proliferation of lung adenocarcinoma cells by regulating microRNA-24 and microRNA-181b

Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

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