2-Methoxyestradiol Analogue ENMD-1198 Reduces Breast Cancer-Induced Osteolysis and Tumor Burden BothIn VitroandIn Vivo

Abstract

It has been estimated that 70% of advanced breast cancer patients will face the complication of bone metastases. Three processes are pivotal during bone metastatic growth of breast cancer, namely, tumor cell proliferation, angiogenesis, and osteolysis. During tumor-induced osteolysis, a number of cytokines and growth factors are released from the degraded bone matrix. These factors stimulate further tumor growth, tumor angiogenesis, and tumor-induced osteolysis. New therapies should target all relevant processes to halt this powerful feedback loop. Here, we characterized the new 2-methoxyestradiol analogue ENMD-1198 and showed that it is cytotoxic to tumor cells. Moreover, ENMD-1198 showed both antiangiogenic and vascular disruptive properties and was capable of protecting the bone against tumor-induced osteolysis. We confirmed the in vitro data with a series of in vivo experiments showing the beneficial effects of ENMD-1198 and ENMD-1198-based combination treatments of metastatic breast cancer in bone both on tumor progression and on survival with long-term ENMD-1198 treatment. We confirmed the in vivo relevance of the ENMD-1198 protective effect on bone both with X-ray radiographs and microcomputed tomography. In addition, we combined ENMD-1198 treatment with low-dose metronomic cyclophosphamide and the bisphosphonate risedronic acid, leading to a mild increase in treatment efficacy. Mol Cancer Ther; 10(5); 874-82. Ó2011 AACR.

Hypoxia‐inducible factor 1‐alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl‐4‐hydroxylase 2

“…The striking effect of HIF‐1α to enhance osteoclast‐mediated bone resorption alternatively suggests HIF inhibition as a strategy to treat osteolytic disease. Administration of the HIF inhibitor 2‐methoxyestradiol (2ME) protected OVX mice from osteoclast activation and bone loss and reduced osteolysis in models of metastatic bone cancer and rheumatoid arthritis . Although 2ME is not a specific inhibitor of HIF, these studies suggest this approach as a promising alternative therapeutic strategy.…”

Signaling Pathways of ESE-16, an Antimitotic and Anticarbonic Anhydrase Estradiol Analog, in Breast Cancer Cells

“…Improved oral bioavailability is argued to be as a result of the potential of aryl sulphamoyl containing compounds to reversibly bind to carbonic anhydrase II present in red blood cells and in turn circumvent first pass liver metabolism [4]. ENMD-1198, another analog of 2ME is undergoing clinical trials and the D-ring modification appears to improve bioavailability when compared to 2ME [5], [6], [7], [8], [9], [10].…”

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

“…Though the central nervous system has been reported to be less susceptible to adverse effects of the chemotherapeutics, cognitive dysfunction has appeared as one of the most alarming adverse effect with a significant influence of patients' quality of life. 2-ME has been confirmed to have anticancer activity both in vivo and in vitro [65][66][67][68][69][70][71]. Due to the evidenced here, neurotoxic and genotoxic effects of pharmacologically relevant concentrations of 2-ME, one may suggest that the patients treated for long periods with the compound may suffer from memory impairment, depressive disorders, or develop functional changes in the hippocampus.…”