Celastrol exerts synergistic effects with PHA-665752 and inhibits tumor growth of c-Met-deficient hepatocellular carcinoma in vivo

Jiang, Honglei; Jin, Junzhe; Wu, Dan; Xu, Dong; Lin, Guang-Tan; Yu, Hao; Ma, Ding; Liang, Jian

doi:10.1007/s11033-013-2501-y

Cited by 26 publications

(16 citation statements)

References 14 publications

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“…daily starting on the day of ONC and continued for 14 days, after which retinas were dissected and analyzed to determine the number of surviving RGCs. The dose of celastrol was chosen based on previous studies in in vivo model systems utilizing this drug (Venkatesha et al, 2011; Jiang et al, 2013; Kim et al, 2013). The number of surviving cells was determined by counting RGCs immunolabeled with Rbpms in flat-mount retinal preparations.…”

Section: Resultsmentioning

confidence: 99%

“…Since this is the first study on the effect of celastrol on the retina and no information on the dosage of this drug for intravitreal injection is available in the literature, three doses were used in these experiments: 1 mg/kg, 0.2 mg/kg and 5 mg/kg. 1 mg/kg concentration was used for the systemic treatment described above (Venkatesha et al, 2011; Jiang et al, 2013; Kim et al, 2013). A single injection of celastrol or DMSO at the time of the ONC procedure was performed to minimize the injury.…”

Section: Resultsmentioning

confidence: 99%

“…I.p. injection of celastrol at this dose has been successfully used in rat and mouse models of various human diseases with no side effects reported (Venkatesha et al, 2011; Jiang et al, 2013; Kim et al, 2013). However, at least two other studies observed a significant decrease in the body weight of animals treated with celastrol (Huang et al, 2012; Kim et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Celastrol supports survival of retinal ganglion cells injured by optic nerve crush

et al. 2015

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The present study evaluates the effect of celastrol on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). Celastrol, a quinine methide triterpene extracted from the perennial vine Tripterygium wilfordii (Celastraceae), has been identified as a potential neuroprotective candidate in a comprehensive drug screen against various neurodegenerative diseases. Two weeks after ONC, the average density of remaining RGCs in retinas of animals treated with daily intraperitoneal (i.p.) injections of celastrol (1 mg/kg) was approximately 1332 cells/mm2, or 40.8% of that of the Celastrol/Control group. In retinas of the Vehicle/ONC group about 381 RGCs/mm2 were counted, which is 9.6% of the total number of RGCs in the DMSO/Control group. This corresponds to approximately a 250% increase in RGC survival mediated by celastrol treatment compared to control. Furthermore, the average RGC number in retinas of ONC animals treated with a single intravitreal injection of 1 mg/kg or 5 mg/kg of celastrol was increased by approximately 80% (760 RGCs/ mm2) and 78% (753 RGCs/mm2), respectively, compared to controls (422 cells/mm2). Injection of 0.2 mg/kg of celastrol had no significant effect on cell survival compared to DMSO-injected controls, with the average number of RGCs being 514 cells/mm2 in celastrol-treated animals versus 422 cells/mm2 in controls. The expression levels of Hsp70, Hsf1, Hsf2, HO-1 and TNF-alpha in the retina were analyzed to evaluate the roles of these proteins in the celastrol-mediated protection of injured RGCs. No statistically significant change in HO-1, Hsf1 and Hsp70 levels was seen in animals with ONC. An approximately 2 fold increase in Hsf2 level was observed in celastrol-treated animals with or without injury. Hsf2 level was also increased 1.8 fold in DMSO-treated animals with ONC injury compared to DMSO-treated animals with no injury suggesting that Hsf2 induction has an injury-induced component. Expression of TNF-alpha in retinas of celastrol-treated uninjured and ONC animals was reduced by approximately 2 and 1.5 fold compared to vehicle treated animals, respectively. The observed results point to the role of TNF-alpha in RGC degeneration following axonal injury, and that suggests mechanisms underlying celastrol’s RGC protective effect is associated with inhibition of TNF-alpha-mediated cell death.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Celastrol supports survival of retinal ganglion cells injured by optic nerve crush

et al. 2015

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“…The natural product celastrol ( Figure ), a pentacyclic triterpene extracted from the roots and barks of Tripterygium wilfordi (thunder god vine) plant, is a natural compound with numerous beneficial pharmacological properties,which including treatment of inflammation, edema, joint pain, rheumatoid arthritis, antimalarial and antitumor. ] The increasing evidence has revealed that celastrol exhibited cytotoxicity against various cancer cell lines in vittro and in vivo , such as pancreatic cancer, hepatocelluar carcinomas, glioma xenografts, prostate cancer, squamous cancer, non‐small cell lung carcinoma. Further studies have showed that the antitumor activities of celastrol may cause by targeting numerous signaling pathways, such as Hsp90, NF‐kB, TNF‐ α , Notch, p‐Akt .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of a Series of Novel Celastrol Derivatives with Amino Acid Chain

Pang

Luo

Liu

et al. 2018

Chemistry & Biodiversity

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The synthesis of celastrol analogues containing amino acid ester at the C(29) position and their evaluation for cytotoxic activities in vitro were reported. The MTT test showed that a set of derivatives with lower IC values than that of the positive control group cisplatin and the parent compound celastrol, which exhibited greater antiproliferative activities. The most potent title compounds 2a and 2e exhibited cytotoxic activities in vitro against HeLa and A549 cell lines with IC values of 0.371 and 0.237 μm, 0.235 and 0.109 μm, respectively. The apoptosis assay demonstrated that 2a and 2e can induces of A549 cell apoptosis in low concentrations. These results showed that 2a and 2e may be promising for further research as antitumor agents.

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“…Celastrol is an active component with many actions, among which are anti-tumor effects. It has been confirmed that celastrol can exert anti-tumor effects both in vitro and in vivo towards a variety of tumor cells with different tissue origins [1-3]. Celastrol’s anti-tumor effects are related to this agent’s ability to arrest the cell cycle and induce apoptosis [2-5].…”

Section: Introductionmentioning

confidence: 99%

Peptide deformylase inhibitor actinonin reduces celastrol’s HSP70 induction while synergizing proliferation inhibition in tumor cells

et al. 2014

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BackgroundCelastrol is a promising anti-tumor agent, yet it also elevates heat shock proteins (HSPs), especially HSP70, this effect believed to reduce its anti-tumor effects. Concurrent use of siRNA to increase celastrol’s anti-tumor effects through HSP70 interference has been reported, but because siRNA technology is difficult to clinically apply, an alternative way to curb unwanted HSP70 elevation caused by celastrol treatment is worth exploring.MethodsIn this work, we explore three alternative strategies to control HSP70 elevation: (1) Searching for cancer cell types that show no HSP70 elevation in the presence of celastrol (thus recommending themselves as suitable targets); (2) Modifying HSP70-inducing chemical groups, i.e.: the carboxyl group in celastrol; and (3) Using signaling molecule inhibitors to specifically block HSP70 elevation while protecting and/or enhancing anti-tumor effects.ResultsThe first strategy was unsuccessful since celastrol treatment increased HSP70 in all 7 of the cancer cell types tested, this result related to HSF1 activation. The ubiquity of HSF1 expression in different cancer cells might explain why celastrol has no cell-type limitation for HSP70 induction. The second strategy revealed that modification of celastrol’s carboxyl group abolished its ability to elevate HSP70, but also abolished celastrol’s tumor inhibition effects. In the third strategy, 11 inhibitors for 10 signaling proteins reportedly related to celastrol action were tested, and five of these could reduce celastrol-caused HSP70 elevation. Among these, the peptide deformylase (PDF) inhibitor, actinonin, could synergize celastrol’s proliferation inhibition.ConclusionsConcurrent use of the chemical agent actinonin could reduce celastrol’s HSP70 elevation and also enhance proliferation inhibition by celastrol. This combination presents a novel alternative to siRNA technology and is worth further investigation for its potentially effective anti-tumor action.

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Celastrol exerts synergistic effects with PHA-665752 and inhibits tumor growth of c-Met-deficient hepatocellular carcinoma in vivo

Cited by 26 publications

References 14 publications

Celastrol supports survival of retinal ganglion cells injured by optic nerve crush

Celastrol supports survival of retinal ganglion cells injured by optic nerve crush

Synthesis and Biological Evaluation of a Series of Novel Celastrol Derivatives with Amino Acid Chain

Peptide deformylase inhibitor actinonin reduces celastrol’s HSP70 induction while synergizing proliferation inhibition in tumor cells

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