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2-Methoxyestradiol Up-Regulates Death Receptor 5 and Induces Apoptosis through Activation of the Extrinsic Pathway

Discovery Research Department, EntreMed, Inc., Rockville, Maryland 20850 [T. M. L., X. H. Z., M. S. J., C. J. H., G. S., W. A. H., S. J. G., V. S. P.], and Department of Immunology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855 [M. S. W.]

2-Methoxyestradiol (2ME₂), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME₂ inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME₂ is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME₂ exerts its effects is still uncertain. This study shows that 2ME₂ uses the extrinsic pathway for induction of apoptosis. 2ME₂ treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME₂-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME₂ to induce apoptosis. Because 2ME₂ administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.

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