2-Methoxyestradiol is a tubulin polymerization inhibitor and also decreases HIF-1 activity. 2-Methoxyestradiol exhibits the inhibitory activity of cellular proliferation in a breast carcinoma cell line MDA-MB-435 and an ovarian carcinoma cell line SK-OV-3 with IC50 of 1.38 μM and 1.79 μM, respectively. 2-Methoxyestradiol induces p53-induced apoptosis via two pathways: activation of p38 and NF-κB; and activation of JNK and AP-1 leading to Bcl-2 phosphorylation. Moreover, 2-Methoxyestradiol ameliorates TGF-β3-induced Smad2/3 phosphorylation and nuclear translocation, and inhibits TGF-β3-induced activation of the PI3K/Akt/mTOR pathway. 2-Methoxyestradiol also upregulates death receptor 5 and binds to tubulin, inhibiting its assembly. Preclinical models also suggest that 2ME2 could also be effective against inflammatory diseases such as rheumatoid arthritis. Several studies have been conducted showing 2ME2 is a microtubule-inhibitor and effective against prostate cancer in rodents.
|Cell lines||MCF-7 and MDA-MB-231 cells|
|Preparation method||Cell culture and cell treatment.
MCF-7 estrogen receptor-positive (ER+ve) human breast cancer cells, MDA-MB-231 ER-negative (ER−ve) human breast cancer cells were obtained from the American Type Culture Collection (LGC Promochem, Teddington, UK). Cells were routinely cultured in RPMI-1640 medium supplemented with 10% (v/v) fetal calf serum, 1% L-glutamine (200 mM), 1% non-essential amino acids (100 ×) and 1% bicarbonate (7.5%) from Sigma and maintained in a humidified incubator under 5% CO2 atmosphere at 37°C. For experiments using hypoxic conditions, cells were incubated under 1% O2 and 5% CO2 atmosphere at 37°C.
|Incubation time||18 h|
|Animal models||mice bearing MCF-7 and MDA-MB-231 xenografts model|
|Formulation||10% tetrahydrofuran: 90% propylene glycol|
|Dosages||40 or 75 mg/kg|
|Administration||orally daily for 28 days|
|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.
|Solubility||DMSO 60 mg/mL|
|Source||Sci Rep (2016). Figure 5. 2-methoxyestradiol (2-ME) was purchased from Abmole|
|Method||CHIP assay and Immunohistochemistry staining|
|Cell Lines||in vivo experiment|
|Incubation Time||30 days|
|Results||Administration of 2-ME and digoxin significantly decreased AngII- mediated HIF-1α, VEGF, MMP-2 and MMP-9 overexpression in the homogenates of the whole aortas, as shown in Fig. 5A. 2-ME and digoxin decreased the AngII induced HIF-1α levels accumulation and elastin degradation in the aorta (Fig. 5B).|
|Source||Sci Rep (2016). Figure 4. 2-methoxyestradiol (2-ME) was purchased from Abmole|
|Method||in vivo experiment|
|Incubation Time||30 days|
|Results||Both non-selective HIF-1α inhibitors 2-ME (25 mg/kg/day, s.c.) and digoxin (1.25 mg/kg/day, i.p.) significantly improved the survival rates (log rank test, n= 20 in each group, p < 0.05, Fig. 4B); decreased the incidences of AAA (0% vs. 84% vs. 35%, vs. 40%, p < 0.01, Fig. 4C), the severities of AAA, in terms of less type III and type IV lesions (43% vs. 15%, vs. 15%, p < 0.05, Fig. 4D) and the external diameters of the aorta (0.67 ± 0.11 mm vs. 1.68.± 0.77 vs. 0.96± 0.30 vs. 1.10± 0.53 mm, p< 0.05, Fig. 4E).|
|Source||Sci Rep (2016). Figure 3. 2-methoxyestradiol (2-ME) was purchased from Abmole|
|Incubation Time||30 min|
|Results||We found that both 2-ME and digoxin attenuated AngII and oxPAPC induced up-regulation of MMP-2 and MMP-9 (n = 5, Fig. 3)|
Sci Rep. 2016 Jul 1;6:28612.
Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases.
2-Methoxyestradiol purchased from AbMole
The In Vitro and In Vivo Activity of the Microtubule Disruptor STX140 Is Mediated by Hif-1 Alpha and CAIX Expression.
Stengel C, et al. Anticancer Res. 2015 Oct;35(10):5249-61. PMID: 26408684.
Mechanism of 2-methoxyestradiol-induced apoptosis and growth arrest in human breast cancer cells.
Fukui M, et al. Mol Carcinog. 2009 Jan;48(1):66-78. PMID: 18521846.
2-Methoxyestradiol, a promising anticancer agent.
Lakhani NJ, et al. Pharmacotherapy. 2003 Feb;23(2):165-72. PMID: 12587805.
2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway.
LaVallee TM, et al. Cancer Res. 2003 Jan 15;63(2):468-75. PMID: 12543804.
2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta.
LaVallee TM, et al. Cancer Res. 2002 Jul 1;62(13):3691-7. PMID: 12097276.
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