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Purity: ≥98%
Cucurbitacin I, a naturally occurring triterpene analog, is a novel, potent and selective inhibitor of JAK2/STAT3 with potent anti-cancer activity on a variety of cancer cell types. autophagy and apoptosis were induced by cucurbitacin I. Exposure of GBM (glioblastoma multiform) cells to cucurbitacin I resulted in pronounced apoptotic cell death through activating bcl-2 family proteins. Cells treatment with cucurbitacin I up-regulated Beclin 1 and triggered autophagosome formation and accumulation as well as conversion of LC3I to LC3II. Activation of the AMP-activated protein kinase/mammalian target of rapamycin/p70S6K pathway, but not the PI3K/AKT pathway, occurred in autophagy induced by cucurbitacin I, which was accompanied by decreased hypoxia-inducible factor 1α. Stable overexpression of hypoxia-inducible factor 1α induced by FG-4497 prevented cucurbitacin I-induced autophagy and down-regulation of bcl-2. Knockdown of beclin 1 or treatment with the autophagy inhibitor 3-methyladenine also inhibited autophagy induced by cucurbitacin I. A coimmunoprecipitation assay showed that the interaction of Bcl-2 and Beclin 1/hVps34 decreased markedly in cells treated with cucurbitacin I. Furthermore, knockdown of beclin 1 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cucurbitacin I-induced apoptosis. Finally, a xenograft model provided additional evidence for the occurrence of cucurbitacin I-induced apoptosis and autophagy in vitro. These findings provide new insights into the molecular mechanisms underlying cucurbitacin I-mediated GBM cell death and may provide an efficacious therapy for patients harboring GBM.
| Targets |
Connective Tissue Growth Factor (CTGF/CCN2)
Transforming Growth Factor-beta (TGF-β) Mitogen-Activated Protein Kinase (MAPK) signaling pathways (ERK1/2, JNK, p38) Smad signaling pathway (Smad2, Smad3, Smad7) |
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| ln Vitro |
The viability of COLO205 cells was considerably decreased upon exposure to cucurbitacin I. Cucurbitacin I inhibits p-STAT3 and MMP-9 expression to produce its anti-cancer effects [1]. Cucurbitacin I pretreatment of cardiomyocytes significantly reduced PE-induced cell expansion and β-MHC and ANF expression. It is noteworthy that cucurbitacin I also inhibits pro-hypertrophic factors, TGF-β/Smad signaling, connective tissue growth factor (CTGF) and MAPK signaling, and these are significant variables impacting fibrosis [2]. When the Jak/Stat3 inhibitor cucurbitacin I was added to Seax cell lines, P-Stat3 and Stat3 levels decreased in a manner that was dependent on both time and concentration. Cucurbitacin I caused a concentration-dependent reduction in Stat3 expression in newly separated Sz cells (n=3), but P-Stat3 was not detected. Ultimately, most (73–91%) tumor cells underwent apoptosis after being incubated with 30 μM cucurbitacin I for 6 hours on newly obtained Sz cells (n=4) [3].
Cucurbitacin I (1 µM) pretreatment significantly attenuated phenylephrine (PE, 100 µM)-induced hypertrophy in neonatal rat cardiomyocytes, as evidenced by reduced cell surface area and suppression of hypertrophic marker genes ANF and β-MHC mRNA expression.[2] Cucurbitacin I (1 µM) downregulated both mRNA and protein expression of CTGF in both control and PE-stimulated cardiomyocytes.[2] Cucurbitacin I (1 µM) inhibited PE-induced phosphorylation (activation) of MAPKs, including ERK1/2, JNK, and p38.[2] Cucurbitacin I (1 µM) suppressed PE-induced upregulation of TGF-β protein expression and phosphorylation of Smad2 and Smad3, while upregulating the expression of the inhibitory Smad7.[2] The anti-hypertrophic effects of Cucurbitacin I were significantly blunted in cardiomyocytes where CTGF or TGF-β1 expression was silenced using specific siRNAs, indicating that its action is mediated through these pathways.[2] |
| ln Vivo |
Throughout the trial, no significant side effects were reported. At the conclusion of the study, the mean tumor volumes were as follows: CQ, 580 mm3 (±107); Cucurbitacin I, 346 mm3 (±79); Combination, 220 mm3 (±62); Control, 616 mm3 (±130). There were notable variations in tumor volume between the groups receiving cucurbitacin I and control, combination and control, and combination and cucurbitacin I. Furthermore, at the conclusion of the study, the average tumor weights of the tumors treated with the combination were significantly lower than those of the control group. Furthermore, the mice's body weight was unaffected [4].
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| Cell Assay |
Cell Viability Assay: Neonatal rat cardiomyocytes were seeded in 96-well plates and treated with Cucurbitacin I at concentrations of 0.1, 0.5, 1, 5, and 10 µM for 24, 48, and 72 hours. Cell viability was assessed using a Cell Counting Kit-8 (CCK-8). Absorbance was measured at 450 nm.[2]
Hypertrophy Induction and Drug Treatment: Neonatal rat cardiomyocytes were pretreated with or without Cucurbitacin I (1 µM) for 24 hours, followed by stimulation with phenylephrine (PE, 100 µM) for an additional 24 hours to induce hypertrophy.[2] Immunofluorescence and Cell Size Measurement: Treated cardiomyocytes grown on coverslips were fixed, permeabilized, and blocked. Cells were incubated with an anti-α-actinin primary antibody overnight at 4°C, followed by an Alexa Fluor 488-conjugated secondary antibody. Cell images were captured using fluorescence microscopy, and cell surface areas were quantified using image analysis software.[2] Quantitative Real-Time PCR (qRT-PCR): Total RNA was isolated from cardiomyocytes. Reverse transcription was performed. qRT-PCR was carried out using SYBR Green chemistry and specific primers for ANF, β-MHC, CTGF, and GAPDH (as an internal control) to measure mRNA expression levels.[2] Western Blot Analysis: Treated cardiomyocytes were lysed. Proteins were separated by SDS-PAGE, transferred to membranes, and probed with specific primary antibodies against CTGF, TGF-β, total and phosphorylated forms of ERK1/2, JNK, p38, Smad2, Smad3, Smad7, and GAPDH (loading control). Proteins were detected using HRP-conjugated secondary antibodies and chemiluminescence. Band intensities were quantified using image analysis software.[2] Gene Silencing with siRNA: Cardiomyocytes were transfected with CTGF-specific siRNA, TGF-β1-specific siRNA, or a scrambled control siRNA using a transfection reagent. After 24 hours, cells were pretreated with Cucurbitacin I and then stimulated with PE.[2] |
| Toxicity/Toxicokinetics |
Cardiomyocyte toxicity: Treatment of neonatal rat cardiomyocytes with cucurbitacin I at concentrations of 0.1 to 1 µM for up to 72 hours did not significantly reduce cell viability. However, treatment with higher concentrations (5 and 10 µM) for 48 or 72 hours significantly reduced cell viability (e.g., after 72 hours of treatment with 10 µM, cell viability decreased to approximately 64% of that in the control group). [2]
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| References |
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| Additional Infomation |
Cucurbitacin I is a cucurbitacin with the chemical name 9,10,14-trimethyl-4,9-cyclo-9,10-open-cholest-2,5,23-triene, substituted with hydroxyl groups at positions 2, 16, 20, and 25, and substituted with oxo groups at positions 1, 11, and 22. It is a plant metabolite and an antitumor drug. It is a cucurbitacin and also a tertiary α-hydroxy ketone. Cucurbitacin I has been reported in Elaeocarpus chinensis, Hemsleya endecaphylla, and other organisms with relevant data. Cucurbitacin I is a naturally occurring triterpenoid compound derived from Cucurbitaceae plants. [2] This study is the first to report the antihypertrophic effect of cucurbitacin I in an in vitro cardiac hypertrophy model. [2] Its mechanism of action may involve inhibition of the CTGF/MAPK and TGF-β/Smad signaling pathways. [2] This study suggests that cucurbitacin I has the potential to be a novel drug for treating cardiac hypertrophy and fibrosis-related diseases. [2]
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| Molecular Formula |
C30H42O7
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|---|---|
| Molecular Weight |
514.6503
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| Exact Mass |
514.293
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| CAS # |
2222-07-3
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| Related CAS # |
Cucurbitacin B;6199-67-3;Cucurbitacin E;18444-66-1
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| PubChem CID |
5281321
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| Appearance |
White to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
716.9±60.0 °C at 760 mmHg
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| Melting Point |
148-150ºC
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| Flash Point |
401.3±29.4 °C
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| Vapour Pressure |
0.0±5.2 mmHg at 25°C
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| Index of Refraction |
1.594
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| LogP |
2.06
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
37
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| Complexity |
1160
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| Defined Atom Stereocenter Count |
8
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| SMILES |
C[C@@]12C[C@H]([C@@H]([C@]1(CC(=O)[C@@]3([C@H]2CC=C4[C@H]3C=C(C(=O)C4(C)C)O)C)C)[C@](C)(C(=O)/C=C/C(C)(C)O)O)O
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| InChi Key |
NISPVUDLMHQFRQ-MKIKIEMVSA-N
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| InChi Code |
InChI=1S/C30H42O7/c1-25(2,36)12-11-21(33)30(8,37)23-19(32)14-27(5)20-10-9-16-17(13-18(31)24(35)26(16,3)4)29(20,7)22(34)15-28(23,27)6/h9,11-13,17,19-20,23,31-32,36-37H,10,14-15H2,1-8H3/b12-11+/t17-,19-,20+,23+,27+,28-,29+,30+/m1/s1
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| Chemical Name |
8S,9R,10R,13R,14S,16R,17R)-17-[(E,2R)-2,6-dihydroxy-6-methyl-3-oxohept-4-en-2-yl]-2,16-dihydroxy-4,4,9,13,14-pentamethyl-8,10,12,15,16,17-hexahydro-7H-cyclopenta[a]phenanthrene-3,11-dione
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| Synonyms |
Cucurbitacin I; Elatericin B; JSI-124; JSI 124; JSI124; NSC 521777; NSC-521777; NSC521777;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~194.31 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9431 mL | 9.7153 mL | 19.4307 mL | |
| 5 mM | 0.3886 mL | 1.9431 mL | 3.8861 mL | |
| 10 mM | 0.1943 mL | 0.9715 mL | 1.9431 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Cucurbitacin I inhibited the growth of GBM cellsin vitroandin vivo.J Biol Chem.2014 Apr 11;289(15):10607-19. |
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Cucurbitacin I induced apoptosis in GBM cells and a xenograft mouse model related to bcl-2 family proteins.J Biol Chem.2014 Apr 11;289(15):10607-19. |
Cucurbitacin I triggered autophagy and activated the autophagy-related gene beclin 1 in GBM cells.J Biol Chem.2014 Apr 11;289(15):10607-19. |
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