生物活性

• 靶点	HIF1α IC50:0.71±0.11μM

• 描述The response of mammalian cells to hypoxia is mediated by a family of transcription factors known as HIF (hypoxia-inducible factors). The subunits of HIF, HIF-1α and HIF-2α are structurally similar and can be degraded rapidly under normoxia. 2-Methoxyestradiol can inhibit HIF-1α and HIF-2α expression, as well as depolymerize microtubules. Treatment with 2-Methoxyestradiol (5 - 100 μM) for 16h can reduce expression of HIF-1α dose-dependently in PC-3 and MDA-MB-231 cells, accompanied with the reduced activity of HIF-1 and the expression of its target protein, VEGF, and without effect on HIF-1α mRNA levels or rate of protein degradation. Treatment with 2-Methoxyestradiol (10 - 100 μM) overnight can depolymerize microtubules and impair nuclear accumulation of HIF-1α in PC-3 cells under hypoxia. Daily oral administration of 2-Methoxyestradiol, 150 mg/kg, for 33 days suppressed tumor growth and angiogenesis, as well as depolymerized microtubules in breast cancer orthotopic models. The inhibition of HIF-2α expression and microtubule-depolymerization by 2-Methoxyestradiol can also be observed in endothelial cells^[1].
• 作用机制2-Methoxyestradiol inhibits the expression, nuclear accumulation and transcriptional activity of HIF-1α^[1]. However, the accurate mechanism of action is unknown now.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  DU145	-	Growth inhibitory assay	-	GI50=1.22 μM	17696419
  DU-145	~100 μM	cytotoxicity assay	-	GI50=1.8 μM	9240348
  HCT-116	~100 μM	cytotoxicity assay	-	GI50=0.47 μM	9240348

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• 动物研究
  剂量	Rat: min = 0.1 mg/kg, max = 75 mg/kg[2] (p.o.); min = 60 mg/kg, max = 600 mg/kg[3] (i.p.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Mice[4] Dose 100 mg/kg Administration p.o. Cmax 190 ng/ml (male) 35 ng/ml (female) Tmax 12 h (male) 30 h (female) F 90% (male) 190% (female) AUC 35.9 µM·min (male) 53.8 µM·min (female)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00394810	Prostate Cancer	Phase 2	Completed	-	United States, Indiana ... more >> Indiana University Cancer Center Indianapolis, Indiana, United States, 46202 United States, Maryland Johns Hopkins University School of Medicine Baltimore, Maryland, United States, 21205 United States, Massachusetts Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, Wisconsin University of Wisconsin Paul P. Carbone Comprehensive Cancer Center Madison, Wisconsin, United States, 53792 Collapse <<
  NCT03617458	Pulmonary Artery Hypertension	Phase 2	Recruiting	December 2022	United States, Tennessee ... more >> Vanderbilt University Medical Center Recruiting Nashville, Tennessee, United States, 37232 Collapse <<
  NCT00444314	Metastatic Renal Cell Carcinom... more >>a Collapse <<	Phase 2	Completed	-	United States, Indiana ... more >> Indiana University Cancer Center Indianapolis, Indiana, United States, 46202 United States, Maryland Johns Hopkins University School of Medicine Baltimore, Maryland, United States, 21205 United States, Wisconsin University of Wisconsin Paul P. Carbone Comprehensive Cancer Center Madison, Wisconsin, United States, 53792 Collapse <<

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• 参考文献

• [1] Mabjeesh NJ, Escuin D, et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell. 2003 Apr;3(4):363-75.

  [2] Sibonga JD, Lotinun S, et al. Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat. Endocrinology. 2003 Mar;144(3):785-92.

  [3] Kang SH, Cho HT, et al. Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model. Cancer Res. 2006 Dec 15;66(24):11991-7.

  [4] Evaluation of the PharmacokineticPharmacodynamic relationship, Metabolism and Plasma Protein Binding of the novel antitumor agent, 2-Methoxyestradiol (2ME2), following oral administration in patients with solid tumors.