SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-02-0376. This Article Full Text (PDF) All Versions of this Article: 2002-02-0376v1 100/6/2187    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chauhan, D. Articles by Anderson, K. C Search for Related Content PubMed PubMed Citation Articles by Chauhan, D. Articles by Anderson, K. C Social Bookmarking                   What's this? Submitted February 5, 2002 Accepted May 2, 2002 2-Methoxyestradiol (2ME2) overcome drug resistance in multiple myeloma cells Dharminder Chauhan, Laurence Catley, Teru Hideshima, Guilan Li, Richard Leblanc, Deepak Gupta, Martin Sattler, Paul Richardson, Robert L Schlossman, Klaus Podar, Edie Weller, Nikhil Munshi, and Kenneth C Anderson* Adult Oncology, Dana Farber Cancer Institute, Boston, MA, USA * Corresponding author; email: Kenneth_Anderson{at}dfci.harvard.edu. 2-Methoxyestradiol (2ME2), an estrogen-derivative, induces growth arrest and apoptosis in leukemic cells and is also antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in MM cell lines and patient cells. Importantly, 2ME2 also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce survival of normal peripheral blood lymphocytes. Moreover, 2ME2 enhances Dex-induced apoptosis and its effect is not blocked by interleukin-6 (IL-6). We next examined the effect of 2ME2 on MM cells in the bone marrow (BM) milieu. 2ME2 decreases survival of BM stromal cells (BMSCs) and secretion of vascular endothelial growth factor (VEGF) as well as IL-6 triggered by adhesion of MM cells to BMSCs. We show that apoptosis induced by 2ME2 is mediated by release of mitochondrial cytochrome-c (cyto-c) and Smac; followed by activation of caspases-8, -9, and -3. Finally, 2ME2 inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies therefore demonstrate that 2ME2 mediates anti-MM activity both directly on MM cells and in the BM microenvironment. They provide the framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and improve outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-M. Renoir, C. Bouclier, A. Seguin, V. Marsaud, and B. Sola Antioestrogen-mediated cell cycle arrest and apoptosis induction in breast cancer and multiple myeloma cells J. Mol. Endocrinol., March 1, 2008; 40(3): 101 - 112. [Abstract] [Full Text] [PDF] D. Chauhan, A. Singh, M. Brahmandam, K. Podar, T. Hideshima, P. Richardson, N. Munshi, M. A. Palladino, and K. C. Anderson Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma Blood, February 1, 2008; 111(3): 1654 - 1664. [Abstract] [Full Text] [PDF] S. V. Rajkumar, P. G. Richardson, M. Q. Lacy, A. Dispenzieri, P. R. Greipp, T. E. Witzig, R. Schlossman, C. F. Sidor, K. C. Anderson, and M. A. Gertz Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma Clin. Cancer Res., October 15, 2007; 13(20): 6162 - 6167. [Abstract] [Full Text] [PDF] S. Kato, A. Sadarangani, S. Lange, M. Villalon, J. Branes, J. J Brosens, G. I Owen, and M. Cuello The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium Endocr. Relat. Cancer, June 1, 2007; 14(2): 351 - 368. [Abstract] [Full Text] [PDF] K. Podar, M. S. Raab, J. Zhang, D. McMillin, I. Breitkreutz, Y.-T. Tai, B. K. Lin, N. Munshi, T. Hideshima, D. Chauhan, et al. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl) Blood, February 15, 2007; 109(4): 1669 - 1677. [Abstract] [Full Text] [PDF] D. Chauhan, P. Neri, M. Velankar, K. Podar, T. Hideshima, M. Fulciniti, P. Tassone, N. Raje, C. Mitsiades, N. Mitsiades, et al. Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM) Blood, February 1, 2007; 109(3): 1220 - 1227. [Abstract] [Full Text] [PDF] K. Podar, G. Tonon, M. Sattler, Y.-T. Tai, S. LeGouill, H. Yasui, K. Ishitsuka, S. Kumar, R. Kumar, L. N. Pandite, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma PNAS, December 19, 2006; 103(51): 19478 - 19483. [Abstract] [Full Text] [PDF] S. A. Salama, A. B. Nasr, R. K. Dubey, and A. Al-Hendy Estrogen Metabolite 2-Methoxyestradiol Induces Apoptosis and Inhibits Cell Proliferation and Collagen Production in Rat and Human Leiomyoma Cells: A Potential Medicinal Treatment for Uterine Fibroids Reproductive Sciences, December 1, 2006; 13(8): 542 - 550. [Abstract] [PDF] D. Chauhan, G. Li, K. Podar, T. Hideshima, P. Neri, D. He, N. Mitsiades, P. Richardson, Y. Chang, J. Schindler, et al. A Novel Carbohydrate-Based Therapeutic GCS-100 Overcomes Bortezomib Resistance and Enhances Dexamethasone-Induced Apoptosis in Multiple Myeloma Cells Cancer Res., September 15, 2005; 65(18): 8350 - 8358. [Abstract] [Full Text] [PDF] T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF] H. Yasui, T. Hideshima, N. Raje, A. M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.-T. Tai, K. Podar, et al. FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance Cancer Res., August 15, 2005; 65(16): 7478 - 7484. [Abstract] [Full Text] [PDF] H. Yasui, T. Hideshima, M. Hamasaki, A. M. Roccaro, N. Shiraishi, S. Kumar, P. Tassone, K. Ishitsuka, N. Raje, Y.-T. Tai, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma Blood, July 15, 2005; 106(2): 706 - 712. [Abstract] [Full Text] [PDF] T. E. Sutherland, M. Schuliga, T. Harris, B. L. Eckhardt, R. L. Anderson, L. Quan, and A. G. Stewart 2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1722 - 1732. [Abstract] [Full Text] [PDF] K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF] B. Lin, L. Catley, R. LeBlanc, C. Mitsiades, R. Burger, Y.-T. Tai, K. Podar, M. Wartmann, D. Chauhan, J. D. Griffin, et al. Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo Blood, January 1, 2005; 105(1): 350 - 357. [Abstract] [Full Text] [PDF] J. L. Ricker, Z. Chen, X. P. Yang, V. S. Pribluda, G. M. Swartz, and C. Van Waes 2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor 1{alpha}, Tumor Growth, and Angiogenesis and Augments Paclitaxel Efficacy in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., December 15, 2004; 10(24): 8665 - 8673. [Abstract] [Full Text] [PDF] M. B. Lens, I. Rosdahl, A. Ahlbom, B. Y. Farahmand, I. Synnerstad, B. Boeryd, and J. A. Newton Bishop Effect of Pregnancy on Survival in Women With Cutaneous Malignant Melanoma J. Clin. Oncol., November 1, 2004; 22(21): 4369 - 4375. [Abstract] [Full Text] [PDF] S. Le Gouill, K. Podar, M. Amiot, T. Hideshima, D. Chauhan, K. Ishitsuka, S. Kumar, N. Raje, P. G. Richardson, J.-L. Harousseau, et al. VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis Blood, November 1, 2004; 104(9): 2886 - 2892. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, K. Podar, T. Hideshima, C. Mitsiades, R. Schlossman, N. Munshi, P. Richardson, F. E. Cotter, and K. C. Anderson Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells Blood, October 15, 2004; 104(8): 2458 - 2466. [Abstract] [Full Text] [PDF] T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, K. Podar, T. Hideshima, R. Shringarpure, L. Catley, C. Mitsiades, N. Munshi, Y. T. Tai, N. Suh, et al. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance Blood, April 15, 2004; 103(8): 3158 - 3166. [Abstract] [Full Text] [PDF] T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al. Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma Cancer Res., December 1, 2003; 63(23): 8428 - 8436. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, T. Hideshima, K. Podar, C. Mitsiades, N. Mitsiades, L. Catley, Y. T. Tai, T. Hayashi, R. Shringarpure, et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance Blood, November 1, 2003; 102(9): 3379 - 3386. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, R. Shringarpure, K. Podar, Y. Ohtake, T. Hideshima, and K. C. Anderson Blockade of Hsp27 Overcomes Bortezomib/Proteasome Inhibitor PS-341 Resistance in Lymphoma Cells Cancer Res., October 1, 2003; 63(19): 6174 - 6177. [Abstract] [Full Text] [PDF] M. Sattler, L. R. Quinnan, Y. B. Pride, J. L. Gramlich, S. C. Chu, G. C. Even, S.-K. Kraeft, L. B. Chen, and R. Salgia 2-Methoxyestradiol alters cell motility, migration, and adhesion Blood, July 1, 2003; 102(1): 289 - 296. [Abstract] [Full Text] [PDF] K. Shimada, M. Nakamura, E. Ishida, M. Kishi, and N. Konishi Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis Carcinogenesis, June 1, 2003; 24(6): 1067 - 1075. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, T. Hideshima, K. Podar, C. Mitsiades, N. Mitsiades, N. Munshi, S. Kharbanda, and K. C. Anderson JNK-dependent Release of Mitochondrial Protein, Smac, during Apoptosis in Multiple Myeloma (MM) Cells J. Biol. Chem., May 9, 2003; 278(20): 17593 - 17596. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, D. Auclair, T. Hideshima, P. Richardson, K. Podar, N. Mitsiades, C. Mitsiades, C. Li, R. S. Kim, et al. Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays Blood, May 1, 2003; 101(9): 3606 - 3614. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020