2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor 1α, Tumor Growth, and Angiogenesis and Augments Paclitaxel Efficacy in Head and Neck Squamous Cell Carcinoma

Abstract

Purpose: Head and neck squamous cell carcinomas have been reported to overexpress hypoxia-inducible factor (HIF)-1␣, a transcription factor that promotes expression of angiogenesis factors and resistance to programmed and therapy-induced cell death. 2-Methoxyestradiol (2ME2) is a natural compound with HIF-1␣ inhibitory activity that is currently being evaluated in phase 1 and 2 clinical trials for advanced solid tumors and multiple myeloma. To our knowledge, this is the first study to evaluate the effects of 2ME2 in head and neck squamous cell carcinoma.Experimental Design: In the present study, we investigated the effects of 2ME2 alone and in combination with paclitaxel, an active agent in recurrent or advanced head and neck squamous cell carcinoma.Results: 2ME2 exhibited antiproliferative and cytotoxic effects in a panel of five head and neck squamous cell carcinoma cell lines in the 0.5 to 10 mol/L range, including induction of G 2 -M blockade, caspase-3/7 activation, and apoptosis at 48 hours. 2ME2 resulted in decreased nuclear HIF-1␣-binding activity and affected the expression of downstream genes, such as bid, a proapoptotic bcl-2 family member, and vascular endothelial growth factor, a proangiogenic cytokine. The up-regulation of Bid (57.5% at 12 hours, P < 0.0006) and inhibition of vascular endothelial growth factor secretion (57.7% at 24 hours, P < 0.015; and 50.3% at 48 hours, P < 0.0006) could be partially attributed to the effects on HIF-1␣, because HIF-1␣ small interfering RNAs produced similar effects. Finally, in vivo, in a xenograft model of head and neck squamous cell carcinoma using UM-SCC-11A cells, 2ME2 exhibited antitumor and antiangiogenic activity, as measured by CD31 immunostaining.Conclusions: These results provide support for the use of 2ME2 in combination with paclitaxel for the treatment of recurrent or advanced head and neck squamous cell carcinoma.

2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor-1α and Suppresses Growth of Lesions in a Mouse Model of Endometriosis

“…It has also been reported that 2-ME 2 decreases nuclear binding activity of HIF-1␣ in head and neck squamous cell carcinoma. 69 In the present study, we showed for the first time that 2-ME 2 inhibits the in vivo expression of HIF-1␣-inducible genes VEGF, Glut-1, and PGK as measured by real-time PCR during the first few hours after transplantation. These results are supported by our findings that HIF-1␣ was also reduced in endometriotic tissues at the protein level.…”

A Comparison and Catalog of Intrinsic Tumor Growth Models

“…Unfortunately, very few data sets exist that allow tumors to grow large enough in order to get a proper estimate of the carrying capacity. We specifically sought out data sets that included data for large populations in order to properly compare the former two models with the latter three (Fujiwara et al, 1993;Takahashi et al, 1992;Murgo, 1985;Richmond et al, 1983;Kisfalvi et al, 2009;Reinmuth et al, 2002;Nakata et al, 1998;Caltagirone et al, 2000;Ricker et al, 2004).…”

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

“…For example, Li et al (2006a,b) showed that the knockdown of HIF-1 α in breast carcinoma cells repressed G 0 /G 1 -phase accumulation and relieved S-phase block, thereby increasing sensitivity to chemotherapy and attenuating tumor growth (Li et al , 2006a,b ). Functional interference with HIF-1 α in various tumor cells has been shown to result in enhanced cell death upon treatment with chemotherapeutic agents (Ricker et al , 2004 ;Peng et al , 2006 ;Hao et al , 2008 ;Sermeus et al , 2008 ;Flamant et al , 2010 ). However, experimentally increasing HIF-1 α enhanced therapy resistance (Ji et al , 2006 ;Martinive et al , 2006 ).…”