ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

Pasquier, Eddy; Sinnappan, Snega; Munoz, Marcia A.; Kavallaris, Maria

doi:10.1158/1535-7163.mct-09-0894

Cited by 47 publications

(44 citation statements)

References 34 publications

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“…This impaired hypoxia sensing increases local concentrations of radical oxygen species, enhancing the proapoptotic effects of these compounds (21,22). In addition, ENMD-1198 interferes with endothelial cell motility, chemotaxis, and morphogenesis into capillary-like structures (22). The results of our in vitro angiogenesis assay and vascular disruption assay confirmed these findings.…”

Section: Discussionsupporting

confidence: 72%

“…This results in a downregulation of VEGF expression and local proangiogenic signaling (21,22,36,37). This impaired hypoxia sensing increases local concentrations of radical oxygen species, enhancing the proapoptotic effects of these compounds (21,22). In addition, ENMD-1198 interferes with endothelial cell motility, chemotaxis, and morphogenesis into capillary-like structures (22).…”

Section: Discussionmentioning

confidence: 99%

“…It displays antiproliferative effects on tumor cells and neoangiogenesis very similar to 2ME2. ENMD-1198 inhibits proangiogenic signaling through downregulating hypoxia-inducible factor I (HIF)-Ia and STAT3, and it has vascular disruptive effects (20)(21)(22). To date, no studies on the treatment of bone metastases or bone-specific effects with ENMD-1198 have been published.…”

Section: Introductionmentioning

confidence: 99%

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

Snoeks

Mol²,

Que³

et al. 2011

Molecular Cancer Therapeutics

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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.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Snoeks

Mol²,

Que³

et al. 2011

Molecular Cancer Therapeutics

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“…2-Methoxyestradiol was one colchicine site agent that was evaluated clinically and had an acceptable toxicity profile, but it failed to advance to US Food and Drug Administration approval because of its low efficacy (Rajku-mar et al, 2007). More metabolically stable 2-methoxyestradiol analogs are now being studied (Pasquier et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

ELR510444, A Novel Microtubule Disruptor with Multiple Mechanisms of Action

Risinger¹,

Westbrook²,

Encinas³

et al. 2010

J Pharmacol Exp Ther

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Although several microtubule-targeting drugs are in clinical use, there remains a need to identify novel agents that can overcome the limitations of current therapies, including acquired and innate drug resistance and undesired side effects. In this study, we show that ELR510444 has potent microtubuledisrupting activity, causing a loss of cellular microtubules and the formation of aberrant mitotic spindles and leading to mitotic arrest and apoptosis of cancer cells. ELR510444 potently inhibited cell proliferation with an IC 50 value of 30.9 nM in MDA-MB-231 cells, inhibited the rate and extent of purified tubulin assembly, and displaced colchicine from tubulin, indicating that the drug directly interacts with tubulin at the colchicine-binding site. ELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in ␤III-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. Our data show a close correlation between the concentration of ELR510444 required for inhibition of cellular proliferation and that required to cause significant loss of cellular microtubule density, consistent with its activity as a microtubule depolymerizer. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. These results suggest that ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy.

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“…In this respect, an active research aims at finding new methods of delivery, mainly based on the encapsulation of 2-ME (Wang et al 2009;Du et al 2010;Mueck and Seeger 2010). Interestingly, the 2-ME analog ENMD-1198 is currently administered orally to oncology patients in a phase I clinical trial (Pasquier et al 2010;Zhou et al 2010). Despite the encouraging results about the beneficial effect in 2-ME in contrasting cancer, the mechanisms at the basis of its pharmacological activity are not fully elucidated.…”

Section: Discussionmentioning

confidence: 99%