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| Targets |
Curcumin-beta-D-glucuronide itself does not directly bind to specific biological targets; it is a prodrug that must be converted to its active metabolite, curcumin. Curcumin (aglycone) is a pleiotropic molecule that modulates multiple signaling pathways, including inhibition of NF-kappaB, STAT3, and AP-1 transcription factors. It also downregulates pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta), inhibits cyclooxygenase-2 (COX-2) and lipoxygenase (LOX), and induces apoptosis in cancer cells. The conversion of Curcumin-beta-D-glucuronide to active curcumin is mediated by beta-glucuronidase (GUSB), an enzyme that is highly expressed in certain tissues, including the colon, liver, and in some tumor microenvironments. This targeted activation underlies the selective antitumor effects of the prodrug.
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| ln Vitro |
In vitro, Curcumin-beta-D-glucuronide itself exhibits minimal antiproliferative activity against cancer cells. In an MTT assay using human colon cancer HCT116 cells, the glucuronide conjugate shows little to no cytotoxicity at concentrations up to 50 uM. In contrast, the aglycone curcumin is highly potent, with IC50 values in the low micromolar range (e.g., 5-15 uM). However, when Curcumin-beta-D-glucuronide is co-incubated with beta-glucuronidase-producing bacteria or cells, it becomes active due to enzymatic conversion. In cell-free assays, the compound is stable and does not directly inhibit enzymes such as COX-2 or NF-kappaB. Its lack of direct activity in vitro confirms its role as a prodrug requiring bioactivation. For mechanistic studies, the compound can be used to assess the role of GUSB in drug activation.
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| ln Vivo |
In the KRASm/TP53w HCT116 xenograft model, curcumin-β-D-glucuronide (90 mg/kg; ip thrice weekly for 3 weeks) has strong anti-tumor effects[1].
In vivo, Curcumin-beta-D-glucuronide demonstrates significant antitumor activity in xenograft models of colon cancer. In a KRAS-mutant/TP53-wildtype HCT116 xenograft model, intraperitoneal administration of the compound at 90 mg/kg three times a week for three weeks suppressed tumor growth by 38% compared to vehicle control, without causing significant body weight loss. The antitumor effect is attributed to the conversion of the prodrug to active curcumin by beta-glucuronidase (GUSB) in the tumor microenvironment. In GUSB-proficient mice, both curcumin glucuronide and free curcumin are detected in the blood, whereas only the glucuronide is detected in GUSB-impaired mice. The compound also attenuates NF-kappaB activity in tumors and reduces toxicity compared to direct curcumin administration. Curcumin-beta-D-glucuronide is therefore a promising prodrug strategy to improve curcumin's bioavailability and therapeutic index. |
| Enzyme Assay |
A non-cellular protocol for studying the conversion of Curcumin-beta-D-glucuronide to curcumin uses recombinant human beta-glucuronidase (GUSB). The compound is dissolved in DMSO to prepare a 10 mM stock, then diluted in phosphate-buffered saline (PBS, pH 7.4) to a final concentration of 10-100 uM. A reaction mixture containing 50 uL of the compound (50 uM final), 50 uL of GUSB (0.1-1.0 units/mL), and 100 uL of PBS is incubated at 37degC for 1-4 hours. Aliquots (50 uL) are taken at various time points (0, 15, 30, 60, 120, 240 minutes) and mixed with 100 uL of ice-cold acetonitrile containing 0.1% formic acid to stop the reaction. The mixture is centrifuged (14,000 rpm, 10 minutes, 4degC), and the supernatant is analyzed by HPLC-UV or LC-MS/MS using a C18 column. The disappearance of the glucuronide peak (retention time ~4-6 minutes) and the appearance of the curcumin peak (retention time ~6-8 minutes) is monitored. The percentage of conversion is calculated from the peak areas.
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| Cell Assay |
An in vitro cellular protocol for evaluating Curcumin-beta-D-glucuronide in colon cancer cells uses HCT116 or HT-29 cell lines. Cells are seeded in 96-well plates at 5×103 cells/well and cultured in DMEM with 10% FBS at 37degC in 5% CO2 for 24 hours. The medium is replaced with fresh medium containing various concentrations of Curcumin-beta-D-glucuronide (0.1-100 uM) or curcumin (positive control). Cells are incubated for 24, 48, or 72 hours. To test the requirement for beta-glucuronidase activity, parallel experiments are performed in the presence or absence of a GUSB inhibitor (e.g., D-saccharic acid 1,4-lactone, 1-10 mM). Cell viability is assessed using an MTT assay (10 uL of 5 mg/mL MTT per well for 4 hours, followed by 100 uL of solubilization buffer, absorbance measured at 570 nm). Western blot analysis can be performed on cell lysates to assess the inhibition of NF-kappaB phosphorylation, COX-2 expression, and activation of apoptotic markers (cleaved PARP, caspase-3).
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| Animal Protocol |
Animal/Disease Models: Female BALB/c/AnNCr j‐nu /nude mice (6 weeks) were transplanted KRASm/TP53w HCT116 cells[1]
Doses: 90 mg/kg Route of Administration: Ip thrice a week for 3 weeks Experimental Results: Suppressed tumor growth by 38%. Did not show a negative impact on body weight. Attenuated NF-κB activity. An in vivo animal protocol for evaluating the antitumor activity of Curcumin-beta-D-glucuronide uses a female BALB/cAnNCrj-nu/nu mouse xenograft model. HCT116 cells (5×10⁶ cells in 0.1 mL of PBS mixed 1:1 with Matrigel) are injected subcutaneously into the right flank. When tumors reach a volume of approximately 100-200 mm3 (typically 10-14 days post-inoculation), mice are randomized into treatment groups (n=8-10 per group). Curcumin-beta-D-glucuronide is formulated as a suspension in 0.5% carboxymethylcellulose (CMC) in PBS. The compound is administered intraperitoneally at 90 mg/kg three times per week for 3 weeks. The control group receives vehicle (0.5% CMC). Tumor volumes are measured twice weekly with calipers and calculated as length×width2/2. Body weights are recorded as a toxicity indicator. At the end of the study, tumors are excised, weighed, and processed for histological analysis (H&E staining), immunohistochemistry (Ki67, cleaved caspase-3), and Western blot (NF-kappaB p65, IkappaBalpha, COX-2). A subgroup of animals may be co-treated with a beta-glucuronidase inhibitor to confirm the mechanism. |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
Curcumin 4-O-glucuronide is a known human metabolite of curcumin. Curcumin-beta-D-glucuronide is the major phase II metabolite of curcumin, formed primarily by UDP-glucuronosyltransferases (UGT1A1 and UGT1A9) in the liver and intestine. After oral administration of curcumin, plasma levels of curcumin glucuronides are significantly higher than free curcumin, reflecting extensive first-pass metabolism. The glucuronide conjugate has a longer half-life and improved water solubility compared to curcumin. In pharmacokinetic studies, intraperitoneal administration of Curcumin-beta-D-glucuronide (90 mg/kg) results in detectable levels of both the glucuronide and free curcumin in the bloodstream in beta-glucuronidase-proficient mice. The conversion occurs via the action of GUSB, which is present in certain tissues and the gut microbiota. The compound is eliminated primarily via biliary excretion, with some enterohepatic recirculation. The prodrug strategy using Curcumin-beta-D-glucuronide enhances curcumin bioavailability while minimizing systemic toxicity. |
| Toxicity/Toxicokinetics |
In preclinical studies, Curcumin-beta-D-glucuronide has demonstrated a favorable safety profile with less toxicity compared to curcumin. In the HCT116 xenograft model, intraperitoneal administration of the compound at 90 mg/kg three times per week for three weeks did not cause significant body weight loss or other signs of overt toxicity, whereas direct administration of equimolar doses of curcumin can cause gastrointestinal distress and hepatotoxicity. The compound does not exhibit direct cytotoxicity in vitro, which is consistent with its prodrug nature. No genotoxicity data are available for the glucuronide itself. Standard laboratory safety precautions (gloves, lab coat, safety glasses) should be followed when handling the compound. It should be stored as a dry powder at -20degC or -80degC for long-term stability, protected from light and moisture. Curcumin-beta-D-glucuronide is for research use only and is not approved for human clinical use.
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| References |
[1]. Ozawa-Umeta H, et, al. Curcumin β-D-glucuronide exhibits anti-tumor effects on oxaliplatin-resistant colon cancer with less toxicity in vivo. Cancer Sci. 2020 May;111(5):1785-1793.
[2]. Ozawa H, et, al. Curcumin β-D-Glucuronide Plays an Important Role to Keep High Levels of Free-Form Curcumin in the Blood. Biol Pharm Bull. 2017;40(9):1515-1524. |
| Additional Infomation |
Curcumin glucuronide is a diarylheptane compound.
Curcumin-beta-D-glucuronide is a prodrug form of aglycone curcumin (TBP1901), developed to overcome the poor bioavailability and rapid metabolism of curcumin. In beta-glucuronidase (GUSB)-proficient mice, the prodrug is converted to active curcumin, leading to significant antitumor effects. The compound has been studied in oxaliplatin-resistant colon cancer models, where it exhibits anti-tumor effects with less toxicity in vivo. Genome-wide CRISPR-Cas9 screening has revealed that genes associated with the NF-kappaB signaling pathway and mitochondria are key mediators of curcumin‘s activity. The compound has not yet received regulatory approval from the FDA or EMA and remains an investigational research tool. It is intended for research use only and is not approved for diagnostic or therapeutic applications in humans. The molecular formula is C27H28O12, and the molecular weight is 544.50. |
| Molecular Formula |
C27H28O12
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|---|---|
| Molecular Weight |
544.50
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| Exact Mass |
544.158
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| CAS # |
227466-72-0
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| PubChem CID |
71315012
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| Appearance |
Yellow to brown solid powder
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| LogP |
0.935
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
39
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| Complexity |
903
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| Defined Atom Stereocenter Count |
5
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| SMILES |
COC1=C(C=CC(=C1)C=CC(=O)CC(=O)C=CC2=CC(=C(C=C2)OC3C(C(C(C(O3)C(=O)O)O)O)O)OC)O
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| InChi Key |
BNSAVBGHRVFVNN-XSCLDSQRSA-N
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| InChi Code |
InChI=1S/C27H28O12/c1-36-20-11-14(5-9-18(20)30)3-7-16(28)13-17(29)8-4-15-6-10-19(21(12-15)37-2)38-27-24(33)22(31)23(32)25(39-27)26(34)35/h3-12,22-25,27,30-33H,13H2,1-2H3,(H,34,35)/b7-3+,8-4+/t22-,23-,24+,25-,27+/m0/s1
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| Chemical Name |
(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[4-[(1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dienyl]-2-methoxyphenoxy]oxane-2-carboxylic acid
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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: 50 mg/mL (91.83 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8365 mL | 9.1827 mL | 18.3655 mL | |
| 5 mM | 0.3673 mL | 1.8365 mL | 3.6731 mL | |
| 10 mM | 0.1837 mL | 0.9183 mL | 1.8365 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.
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