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2-methoxyestradiol

2-methoxyestradiol is an orally bioavailable estradiol metabolite with potential antineoplastic activity. 2-Methoxyestradiol inhibits angiogenesis by reducing endothelial cell proliferation and inducing endothelial cell apoptosis. This agent also inhibits tumor cell growth by binding to tubulin, resulting in antimitotic activity, and by inducing caspase activation, resulting in cell cycle arrest in the G2 phase, DNA fragmentation, and apoptosis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    EntreMed, Inc.

2-Methoxyestradiol (2ME2) is a drug that prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis). It is derived from estrogen, although it binds poorly to known estrogen receptors, and belongs to the family of drugs called angiogenesis inhibitors. It has undergone Phase 1 clinical trials against breast cancers. Preclinical models also suggest that 2ME2 could also be effective against inflammatory diseases such as rheumatoid arthritis. The CAS name for 2ME2 is (17 beta)-2-methoxyestra-1,3,5(10)-triene-3,17-diol. It also acts as a vasodilator. Several studies have been conducted showing 2ME2 is a microtubule-inhibitor and effective against prostate cancer in rodents. see http://en.wikipedia.org/wiki/2-methoxyestradiol.

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2: Kambhampati S, Banerjee S, Dhar K, Mehta S, Haque I, Dhar G, Majumder M, Ray G, Vanveldhuizen PJ, Banerjee SK. 2-methoxyestradiol inhibits Barrett's esophageal adenocarcinoma growth and differentiation through differential regulation of the beta-catenin-E-cadherin axis. Mol Cancer Ther. 2010 Mar;9(3):523-34. Epub 2010 Mar 2. PubMed PMID: 20197389; PubMed Central PMCID: PMC2837538.

3: Guo XH, Zhang N, Cui FD, Du B, Zhang ZZ. An investigation on intestinal absorption of a new anticancer drug, 2-methoxyestradiol. Pharmazie. 2009 Nov;64(11):748-51. PubMed PMID: 20099520.

4: Chua YS, Chua YL, Hagen T. Structure activity analysis of 2-methoxyestradiol analogues reveals targeting of microtubules as the major mechanism of antiproliferative and proapoptotic activity. Mol Cancer Ther. 2010 Jan;9(1):224-35. Epub 2010 Jan 6. PubMed PMID: 20053769.

5: Foster PA, Ho YT, Newman SP, Leese MP, Potter BV, Reed MJ, Purohit A. STX140 and STX641 cause apoptosis via the intrinsic mitochondrial pathway and down-regulate survivin and XIAP expression in ovarian and prostate cancer cells. Anticancer Res. 2009 Oct;29(10):3751-7. PubMed PMID: 19846905.

6: Lorin S, Borges A, Ribeiro Dos Santos L, Souquère S, Pierron G, Ryan KM, Codogno P, Djavaheri-Mergny M. c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells. Cancer Res. 2009 Sep 1;69(17):6924-31. Epub 2009 Aug 25. PubMed PMID: 19706754.

7: Chen CH, Lee WJ, Chang TC, Chen RJ, Chien CH, Chow SN. Antiproliferative effects of 2-methoxyestradiol alone and in combination with chemotherapeutic agents on human endometrial cancer cells. Eur J Gynaecol Oncol. 2009;30(3):275-80. PubMed PMID: 19697620.

8: Hou Y, Meyers CY, Akomeah M. A short, economical synthesis of 2-methoxyestradiol, an anticancer agent in clinical trials. J Org Chem. 2009 Aug 21;74(16):6362-4. PubMed PMID: 19610601.

9: Wang SH, Shi X, Chen X, Baker JR Jr. Therapeutic efficacy of 2-methoxyestradiol microcrystals encapsulated within polyelectrolyte multilayers. Macromol Biosci. 2009 May 13;9(5):429-36. PubMed PMID: 19370749; PubMed Central PMCID: PMC2901834.

10: Foster PA, Stengel C, Ali T, Leese MP, Potter BV, Reed MJ, Purohit A, Newman SP. A comparison of two orally bioavailable anti-cancer agents, IRC-110160 and STX140. Anticancer Res. 2008 May-Jun;28(3A):1483-91. PubMed PMID: 18630502.

11: Foster PA, Newman SP, Leese MP, Bernetiere S, Diolez C, Camara J, Hacher B, Baronnet MM, Ali T, Potter BV, Reed MJ, Purohit A. A new micronized formulation of 2-methoxyestradiol-bis-sulfamate (STX140) is therapeutically potent against breast cancer. Anticancer Res. 2008 Mar-Apr;28(2A):577-81. PubMed PMID: 18506995.

12: Edsall AB, Agoston GE, Treston AM, Plum SM, McClanahan RH, Lu TS, Song W, Cushman M. Synthesis and in vivo antitumor evaluation of 2-methoxyestradiol 3-phosphate, 17-phosphate, and 3,17-diphosphate. J Med Chem. 2007 Dec 27;50(26):6700-5. Epub 2007 Dec 6. PubMed PMID: 18052315.

13: Casadei MA, Pitarresi G, Calabrese R, Paolicelli P, Giammona G. Biodegradable and pH-sensitive hydrogels for potential colon-specific drug delivery: characterization and in vitro release studies. Biomacromolecules. 2008 Jan;9(1):43-9. Epub 2007 Dec 1. PubMed PMID: 18052027.

14: Van Veldhuizen PJ, Ray G, Banerjee S, Dhar G, Kambhampati S, Dhar A, Banerjee SK. 2-Methoxyestradiol modulates beta-catenin in prostate cancer cells: a possible mediator of 2-methoxyestradiol-induced inhibition of cell growth. Int J Cancer. 2008 Feb 1;122(3):567-71. PubMed PMID: 17935127.

15: Xia GH, Chen BA, Lu HX, Ding JH, Shao ZY, Gao C. [Alterations of telomerase activity and apoptosis induced by 2-methoxyestradiol in human myelodysplastic syndrome cell line MUTZ-1]. Zhonghua Xue Ye Xue Za Zhi. 2007 Mar;28(3):199-202. Chinese. PubMed PMID: 17649715.

16: Xia GH, Chen BA, Shao ZY, Lu HX, Konstanze D, Hartmut D. Mechanism of 2-methoxyestradiol-induced apoptosis in myelodysplastic syndrome MUTZ-1 cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Apr;15(2):296-301. PubMed PMID: 17493335.

17: Lakhani NJ, Sparreboom A, Xu X, Veenstra TD, Venitz J, Dahut WL, Figg WD. Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2-methoxyestradiol. J Pharm Sci. 2007 Jul;96(7):1821-31. PubMed PMID: 17252610.

18: Lakhani N, Sparreboom A, Venitz J, Dahut WL, Figg WD. Plasma protein binding of the investigational anticancer agent 2-methoxyestradiol. Anticancer Drugs. 2006 Sep;17(8):977-83. PubMed PMID: 16940808.

19: Hirai Y, Kawabe N, Tsuda Y, Miyamoto S, Iwakawa S. Effect of 2-methoxyestradiol, buthionine sulfoximine and hydrogen peroxide on the viability of renal carcinoma cell lines (ACHN and ACVB). Biol Pharm Bull. 2006 May;29(5):1064-7. PubMed PMID: 16651749.

20: Shi X, Wang S, Chen X, Meshinchi S, Baker JR Jr. Encapsulation of submicrometer-sized 2-methoxyestradiol crystals into polymer multilayer capsules for biological applications. Mol Pharm. 2006 Mar-Apr;3(2):144-51. PubMed PMID: 16579643.

21: Ray G, Dhar G, Van Veldhuizen PJ, Banerjee S, Saxena NK, Sengupta K, Banerjee SK. Modulation of cell-cycle regulatory signaling network by 2-methoxyestradiol in prostate cancer cells is mediated through multiple signal transduction pathways. Biochemistry. 2006 Mar 21;45(11):3703-13. PubMed PMID: 16533053.

22: Dahut WL, Lakhani NJ, Gulley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Nguyen D, Yang SX, Steinberg SM, Venitz J, Sparreboom A, Figg WD. Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biol Ther. 2006 Jan;5(1):22-7. Epub 2006 Jan 22. PubMed PMID: 16357512.

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24: Nguyen TL, McGrath C, Hermone AR, Burnett JC, Zaharevitz DW, Day BW, Wipf P, Hamel E, Gussio R. A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach. J Med Chem. 2005 Sep 22;48(19):6107-16. Erratum in: J Med Chem. 2005 Dec 1;48(24):7917. PubMed PMID: 16162011.

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26: Liu ZJ, Lee WJ, Zhu BT. Selective insensitivity of ZR-75-1 human breast cancer cells to 2-methoxyestradiol: evidence for type II 17beta-hydroxysteroid dehydrogenase as the underlying cause. Cancer Res. 2005 Jul 1;65(13):5802-11. PubMed PMID: 15994956.

27: Li L, Da J, Landström M, Ulmsten U, Fu X. Antiproliferative activity and toxicity of 2-methoxyestradiol in cervical cancer xenograft mice. Int J Gynecol Cancer. 2005 Mar-Apr;15(2):301-7. PubMed PMID: 15823116.

28: Han GZ, Liu ZJ, Shimoi K, Zhu BT. Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer. Cancer Res. 2005 Jan 15;65(2):387-93. PubMed PMID: 15695378.

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30: Hagen T, D'Amico G, Quintero M, Palacios-Callender M, Hollis V, Lam F, Moncada S. Inhibition of mitochondrial respiration by the anticancer agent 2-methoxyestradiol. Biochem Biophys Res Commun. 2004 Sep 24;322(3):923-9. PubMed PMID: 15336552.

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32: Ireson CR, Chander SK, Purohit A, Perera S, Newman SP, Parish D, Leese MP, Smith AC, Potter BV, Reed MJ. Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxyoestradiol-bis-sulphamate in vivo in rodents. Br J Cancer. 2004 Feb 23;90(4):932-7. PubMed PMID: 14970876; PubMed Central PMCID: PMC2410173.

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37: Sattler M, Quinnan LR, Pride YB, Gramlich JL, Chu SC, Even GC, Kraeft SK, Chen LB, Salgia R. 2-methoxyestradiol alters cell motility, migration, and adhesion. Blood. 2003 Jul 1;102(1):289-96. Epub 2003 Mar 13. PubMed PMID: 12637335.

38: Lakhani NJ, Sarkar MA, Venitz J, Figg WD. 2-Methoxyestradiol, a promising anticancer agent. Pharmacotherapy. 2003 Feb;23(2):165-72. Review. PubMed PMID: 12587805.

39: Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood. 2003 May 15;101(10):4098-104. Epub 2003 Jan 16. PubMed PMID: 12531810.

40: Cushman M, Mohanakrishnan AK, Hollingshead M, Hamel E. The effect of exchanging various substituents at the 2-position of 2-methoxyestradiol on cytotoxicity in human cancer cell cultures and inhibition of tubulin polymerization. J Med Chem. 2002 Oct 10;45(21):4748-54. PubMed PMID: 12361402.

41: Gołebiewska J, Rozwadowski P, Spodnik JH, Knap N, Wakabayashi T, Woźniak M. Dual effect of 2-methoxyestradiol on cell cycle events in human osteosarcoma 143B cells. Acta Biochim Pol. 2002;49(1):59-65. PubMed PMID: 12136957.

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43: Schumacher G, Neuhaus P. The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors. J Cancer Res Clin Oncol. 2001 Jul;127(7):405-10. Review. PubMed PMID: 11469676.

44: MacCarthy-Morrogh L, Townsend PA, Purohit A, Hejaz HAM, Potter BVL, Reed MJ, Packham G. Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest, apoptosis, and microtubule assembly in human breast cancer cells. Cancer Res. 2000 Oct 1;60(19):5441-50. PubMed PMID: 11034086.

45: Cushman M, He HM, Katzenellenbogen JA, Varma RK, Hamel E, Lin CM, Ram S, Sachdeva YP. Synthesis of analogs of 2-methoxyestradiol with enhanced inhibitory effects on tubulin polymerization and cancer cell growth. J Med Chem. 1997 Jul 18;40(15):2323-34. PubMed PMID: 9240348.