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Purity: ≥98%
Trabectedin (also known as ET743; Ecteinascidin-743; ET-743; trade name Yondelis) is a novel antitumor agent of marine origin with potent in vitro and in vivo antitumour activity. It has been authorized as an antitumor chemotherapy drug as of 2015 for the treatment of ovarian cancer and advanced soft-tissue sarcoma. In both types of breast cancer cells, trabectedin caused cytotoxicity and apoptosis in a time- and concentration-dependent manner.
Trabectedin is a tetrahydroisoquinoline alkaloid obtained from a Caribbean tunicate Ecteinascidia turbinata. Used for the treatment of soft tissue sarcoma and relapsed ovarian cancer. It has a role as an antineoplastic agent, a marine metabolite, an anti-inflammatory agent, an angiogenesis modulating agent and an alkylating agent. It is an organic heteropolycyclic compound, an azaspiro compound, an oxaspiro compound, a bridged compound, a lactone, a polyphenol, an acetate ester, a hemiaminal, an organic sulfide, a tertiary amino compound and an isoquinoline alkaloid.| Targets |
MX-1 cells (IC50 = 0.1 nM); MCF7 cells (IC50 = 1.5 nM); MCF7/DXR cells (IC50 = 3.7 nM); Reactive oxygen species (ROS); Apoptosis
Trabectedin binds to the minor groove of DNA, particularly guanine-rich sequences, and functions as a DNA alkylating agent [2] Trabectedin exhibits anti-proliferative activity in MCF-7 cells (IC50 = 1.5 nM) and MDA-MB-453 cells [2] |
|---|---|
| ln Vitro |
Treatment with trabectedin (ET-743; 10 nM; 24-72 hours; MCF7 cells) causes cell accumulation in the late S to G2 phase[1].
Trabectedin has an IC50 of 0.1 nM, 1.5 nM, and 3.7 nM, respectively, which inhibits the growth of MX-1, MCF7, and MCF7/DXR cells[1]. Trabectedin causes cytotoxicity and apoptosis in both types of breast cancer cells in a manner that depends on both time and concentration. When Trabectedin is applied to MCF-7 cells, the expression levels of the death receptor pathway molecules TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD are significantly increased by 2.6, 3.1, 1.7, 11.2, and 4.0 fold, respectively. Pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and cleaved Caspase-3 expression levels are increased by 4.2, 3.6, 4.8, 4.5, and 4.4 fold in MDA-MB-453 cells, whereas anti-apoptotic protein expression levels Bcl-2 and Bcl-XL are decreased by 4.8 and 5.2 fold[2]. Myxoid liposarcoma (MLS) primary tumor cultures and/or cell lines can produce CCL2, CXCL8, IL-6, VEGF, and PTX3 when treated in vitro with noncytotoxic concentrations of Trabectedin[3]. In human breast cancer cell lines, trabectedin (ET-743) showed sequence-dependent synergistic cytotoxicity when combined with NSC 125973. The combination enhanced cell growth inhibition compared to single-agent treatment, with maximal synergy observed when trabectedin was administered prior to NSC 125973 [1] In MCF-7 (HER2-/ER+) cells, trabectedin induced apoptosis by upregulating death receptor pathway molecules: TRAIL-R1/DR4 (2.6-fold), TRAIL-R2/DR5 (3.1-fold), FAS/TNFRSF6 (1.7-fold), TNF RI/TNFRSF1A (11.2-fold), and FADD (4.0-fold). In MDA-MB-453 (HER2+/ER-) cells, it activated the mitochondrial pathway by increasing pro-apoptotic proteins Bax (4.2-fold), Bad (3.6-fold), cytochrome c (4.8-fold), Smac/DIABLO (4.5-fold), and cleaved caspase-3 (4.4-fold), while reducing anti-apoptotic Bcl-2 (4.8-fold) and Bcl-XL (5.2-fold). Reactive oxygen species (ROS) generation was increased in both cell lines [2] In human myxoid liposarcoma (MLS) cells, non-cytotoxic concentrations of trabectedin selectively inhibited the production of pro-inflammatory factors (CCL2, CXCL8, IL-6), VEGF, and PTX3 [3] |
| ln Vivo |
Treatment with trabectin (ET-743; 30-50 μg/kg; intravenous injection; every three days; female athymic nude mice) increases the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity[1].
Following Trabectedin treatment, CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decreases in PTX3 are significantly reduced in a xenograft mouse model of human myxoid liposarcoma (MLS)[3]. In a xenograft mouse model of human breast cancer, trabectedin alone inhibited tumor growth, and its combination with NSC 125973 further reduced tumor volume in a sequence-dependent manner (superior when trabectedin was administered first) [1] In a human MLS xenograft model, trabectedin treatment significantly reduced CCL2, CXCL8, CD68+ infiltrating macrophages, and CD31+ tumor vessels, with a partial decrease in PTX3 [3] |
| Cell Assay |
Breast cancer cells were seeded in culture plates and treated with trabectedin alone or in combination with NSC 125973 at varying concentrations and sequences. Cell viability was assessed using standard cytotoxicity assays, and synergism was analyzed by combination index calculations [1]
MCF-7 and MDA-MB-453 cells were exposed to trabectedin at concentrations ranging from 0.1 to 100 nM for 24–72 hours. Apoptosis was detected by flow cytometry, and protein expression levels were measured by western blot analysis of cell lysates [2] MLS primary cultures and cell lines were treated with non-cytotoxic doses of trabectedin. Cytokine and growth factor levels (CCL2, CXCL8, IL-6, VEGF, PTX3) in culture supernatants were quantified by immunoassays [3] Before samples were collected for Western blot analysis, RNAiMax Lipofectamine (4.5 mL per well in a 6-well dish) was added to siRNA targeting the EWS-FLI1 breakpoint site II, complexed, combined with cells, and incubated for 36 to 48 hours. |
| Animal Protocol |
Female nude mice bearing human breast cancer xenografts were randomized to receive trabectedin (dose not specified) alone, NSC 125973 alone, or their combination in different sequences. Drugs were administered via intravenous injection, and tumor volume was measured twice weekly [1]
Nude mice with MLS xenografts were treated with trabectedin (dose not specified) via intravenous injection. Tumor tissues were collected after treatment to assess cytokine levels, macrophage infiltration, and vessel density by immunohistochemistry [3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Administered intravenously. Biological Half-Life 33-50 hours |
| Toxicity/Toxicokinetics |
Hepatotoxicity
Elevations in serum aminotransferase levels arise in almost all patients treated with trabectedin and elevations above 5 times the upper limit of normal occur 20% to 50% of patients. Pretreatment with dexamethasone appears to decrease the degree and frequency of enzyme elevations. The elevations arise within 2 to 5 days of the intravenous infusion, rise to maximal levels between 5 and 9 days and generally fall to baseline values within 3 to 4 weeks. Minor elevations in serum alkaline phosphatase and bilirubin are also common. However, clinically apparent liver injury with jaundice from trabectedin is rare. On the other hand, patients with underlying liver disease appear to be at increased risk for septicemia and multiorgan failure, and monitoring of liver tests before and during therapy is recommended. The liver injury typically mimics acute decompensation of an underlying cirrhosis with modest elevations in serum enzymes and worsening jaundice and hepatic synthetic dysfunction. Immunoallergic and autoimmune features are uncommon. Fatalities are generally due to sepsis and multiorgan failure. Likelihood score: C[HD] (probable cause of clinically apparent liver injury, generally in the setting of preexisting liver disease and use of high doses). Protein Binding 94 to 98% |
| References |
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| Additional Infomation |
Trabectedin (ET-743; Ecteinascidin-743) is a marine-derived tetrahydroisoquinoline alkaloid with antitumor activity [2][3]
The synergistic effect of trabectedin and NSC 125973 in breast cancer cells is sequence-dependent, likely due to differential effects on DNA damage repair pathways [1] In MLS cells, trabectedin exerts both direct antitumor effects and indirect anti-inflammatory/anti-angiogenic activities [3] 1. Drug origin and structure: Trabectedin (ET743; Ecteinascidin-743) is a semi-synthetic tetrahydroisoquinoline alkaloid, originally isolated from the marine tunicate Ecteinascidia turbinata. Its chemical structure enables specific binding to the DNA minor groove, which is the basis for its antitumor activity [2] 2. Apoptosis mechanism specificity: Trabectedin (ET743; Ecteinascidin-743) induces apoptosis in a genotype-dependent manner in breast cancer cells: it activates the extrinsic death receptor pathway in HER2-/ER+ MCF-7 cells and the intrinsic mitochondrial pathway in HER2+/ER- MDA-MB-453 cells. This specificity suggests potential tailored treatment strategies based on tumor molecular subtypes [2] 3. Anti-inflammatory mechanism hypothesis: The anti-inflammatory effects of Trabectedin (ET743; Ecteinascidin-743) in human myxoid liposarcoma cells may be mediated by inhibition of the NF-κB signaling pathway (via reduced p65 nuclear translocation), which contributes to its overall antitumor activity by suppressing the pro-tumor inflammatory microenvironment [3] 4. Combination therapy implication: The sequence-dependent synergism between Trabectedin (ET743; Ecteinascidin-743) and NSC 125973 in breast cancer models highlights the importance of treatment ordering in combination regimens, which may guide clinical trial design for combination therapies involving Trabectedin [1] Pharmacodynamics Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. |
| Molecular Formula |
C39H43N3O11S
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|---|---|
| Molecular Weight |
761.843
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| Exact Mass |
761.261
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| Elemental Analysis |
C, 61.49; H, 5.69; N, 5.52; O, 23.10; S, 4.21
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| CAS # |
114899-77-3
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| Related CAS # |
Trabectedin-d3
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| PubChem CID |
108150
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| Appearance |
White to light yellow solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.732
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
15
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
54
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| Complexity |
1450
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| Defined Atom Stereocenter Count |
7
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| SMILES |
CC1=C(OCO2)C2=C([C@H](COC3=O)N4[C@]([C@@H]5SC[C@]63C(C=C(OC)C(O)=C7)=C7CCN6)([H])[C@@H]8N(C)[C@@H](CC9=CC(C)=C(OC)C(O)=C98)[C@@H]4O)C5=C1OC(C)=O
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| InChi Key |
PKVRCIRHQMSYJX-RJZIEWFPSA-N
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| InChi Code |
InChI=1S/C39H43N3O11S/c1-16-9-20-10-22-37(46)42-23-13-50-38(47)39(21-12-25(48-5)24(44)11-19(21)7-8-40-39)14-54-36(30(42)29(41(22)4)26(20)31(45)32(16)49-6)28-27(23)35-34(51-15-52-35)17(2)33(28)53-18(3)43/h9,11-12,22-23,29-30,36-37,40,44-46H,7-8,10,13-15H2,1-6H3/t22-,23-,29+,30+,36+,37-,39+/m0/s1
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| Chemical Name |
[(1R,2R,3R,11S,12S,14R,26R)-5,6',12-trihydroxy-6,7'-dimethoxy-7,21,30-trimethyl-27-oxospiro[17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.13,11.02,13.04,9.015,23.016,20]triaconta-4(9),5,7,15,20,22-hexaene-26,1'-3,4-dihydro-2H-isoquinoline]-22-yl] acetate
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| Synonyms |
Trabectedin; ET-743; ET 743; 114899-77-3; Yondelis; Ecteinascidin; ecteinascidin 743; ET743; Ecteinascidin 743
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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 Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. (3). This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| 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: 33.3~100 mg/mL (43.8~131.3 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.28 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.28 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (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 | 1.3126 mL | 6.5631 mL | 13.1261 mL | |
| 5 mM | 0.2625 mL | 1.3126 mL | 2.6252 mL | |
| 10 mM | 0.1313 mL | 0.6563 mL | 1.3126 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.
Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors
CTID: NCT03127215
Phase: Phase 2 Status: Completed
Date: 2024-05-08
Products are for research use only; We do not sell to patients
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