Celastrol down-regulated the basal and DNA damaging agents-induced monoubiquitination of FANCD2,followed by proteolytic degradation. Celastrol treatment abrogated the G2 checkpoint induced by IR,and enhanced the ICL agents-induced DNA damage and inhibitory effects on lung cancer cells through depletion of FANCD2.Celastrol presented striking growth inhibition and apoptosis induction potency on DU145 cells in vitro in a time- and dose-dependent manner.Celastrol exhibits its antiprostate cancer effects partially through the downregulation of the expression level of hERG channel in DU145 cells,suggesting that celastrol may be a potential agent against prostate cancer with a mechanism of blocking the hERG channel.Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy by suppressing the PI3K/Akt/mTOR signaling pathway.Celastrol has the potential to inhibit cytochrome P450 activities and may cause the herb-drug interactions.Celastrol induces apoptosis in TNBC cells and indicated that apoptosis might be mediated through mitochondrial dysfunction and PI3K/Akt signaling pathway.
|Cell lines||RPMI 8226, KATOIII, UM-SCC1, U251MG and MDA-MB-231 cells|
|Preparation method||Determining the anti-proliferative effect of celastrol on various human tumor cell lines by the MTT uptake method. Briefly, incubating 5×103 cells with Celastrol in triplicate in a 96-well plate at 37 ℃. Then adding MTT solution to each well. After a 2 hours incubation at 37 ℃, adding extraction buffer (20% SDS, 50% dimethylformamide) , incubating cells overnight at 37 ℃, and then measuring the optical density at 570 nm using a Tecan plate reader.|
|Incubation time||2 hours|
|Animal models||nude mice bearing C4-2B tumors|
|Formulation||10% DMSO, 70% Cremophor/ethanol (3:1), and 20% PBS|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Celastrol overcomes HSP72 gene silencing-mediated muscle atrophy and induces myofiber preservation.
Gwag T, et al. J Physiol Pharmacol. 2015 Apr;66(2):273-83. PMID: 25903958.
Celastrol induces proteasomal degradation of FANCD2 to sensitize lung cancer cells to DNA crosslinking agents.
Wang GZ, et al. Cancer Sci. 2015 Apr 18. PMID: 25891850.
Effect of Celastrol on Growth Inhibition of Prostate Cancer Cells through the Regulation of hERG Channel In Vitro.
Ji N, et al. Biomed Res Int. 2015;2015:308475. PMID: 25866772.
Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy.
Zhao J, et al. Int Immunopharmacol. 2015 May;26(1):221-8. PMID: 25858875.
Anticancer effect of celastrol on human triple negative breast cancer: Possible involvement of oxidative stress, mitochondrial dysfunction, apoptosis and PI3K/Akt pathways.
Shrivastava S, et al. Exp Mol Pathol. 2015 Mar 26;98(3):313-327. PMID: 25818165.
Inhibitory mechanisms of celastrol on human liver cytochrome P450 1A2, 2C19, 2D6, 2E1 and 3A4.
Jin C, et al. Xenobiotica. 2015 Mar 26;1-7. PMID: 25811791.
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CH5138303 is an orally available Hsp90 inhibitor with Kd of 0.48 nM.
Retaspimycin is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90).
KW-2478 is a nonansamycin HSP90 inhibitor with IC50 of 3.8 nM.
Geldanamycin is a natural existing HSP90 inhibitor with Kd of 1.2 μM, specifically disrupts glucocorticoid receptor (GR)/HSP association.
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