Potentiation of 2-methoxyestradiol-induced cytotoxicity by blocking endothelin A receptor in prostate cancer cells.
ABSTRACT 2-Methoxyestradiol (2ME2) is an antitumoral and antiangiogenic compound that inhibits hypoxia-inducible factor (HIF)-1, a key regulator of the hypoxic response that promotes tumor progression. HIF-1alpha, the regulated subunit of HIF-1, is overexpressed in premalignant, cancerous and metastatic lesions of prostate. Endothelin (ET)-1 is a HIF target gene and one that plays an important role during prostate bone metastasis via its interaction with endothelin A (ET(A)) receptor. We reasoned that 2ME2 combined with an ET(A) receptor antagonist would induce potent cytotoxic effects in prostate cancer cells.
PC-3 and LNCaP cells were grown alone or cocultured with human osteoblasts. The cells were treated with 2ME2, with an ET(A) receptor antagonist (BQ-123) or with combinations of both compounds. The cells were then evaluated for cytotoxicity, HIF-1alpha protein expression and HIF-1 transcriptional activity.
The combination of 2ME2 with BQ-123 induced synergistic cytotoxic effects in prostate cancer cells and in their cocultures with osteoblasts. No synergism was observed when 2ME2 was combined with the ET(B) selective antagonist, BQ-788. These results correlated with inhibition of HIF-1alpha protein expression, HIF-1 transcriptional activity, and PSA mRNA expression.
The ET(A) receptor antagonist was capable of potentiating the cytotoxic effects of 2ME2 in prostate cancer cells. These effects were apparently mediated through the inhibition of the HIF-1 pathway. Our in vitro data strengthen the rationale for using 2ME2 in combination with ET(A) receptor antagonists for the treatment of metastatic prostate cancer.
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ABSTRACT: In human papillomavirus (HPV)-positive cervical cancer cells, the endothelin A receptor (ET(A)R) mediates an endothelin-1-induced mitogenic effect, thus representing a relevant target for antitumor therapy. Here, we describe the complete inhibition of human cervix carcinoma growth by blocking the ET(A)R. In nude mice, the ET(A)R-selective antagonist atrasentan inhibits the growth and the neoangiogenesis of cervical carcinoma cell xenografts. Two cycles of treatment completely revert tumor growth. Atrasentan displays additive effects when administered in combination with the cytotoxic drug paclitaxel. These results demonstrate that by inhibiting cell proliferation and angiogenesis, this small molecule may help to control cervical cancer by either monotherapy or combination therapy.Cancer Research 12/2002; 62(22):6381-4. · 8.65 Impact Factor
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ABSTRACT: The objective of the present study was to localize endothelin receptors in the human prostate using quantitative autoradiography. Slide-mounted tissue sections 20 microns. in thickness were obtained from the transition zones of seven patients undergoing radical prostatectomies for low volume prostate cancer. Sarafotoxin (S6C) and BQ123 have been used to distinguish endothelin receptor subtypes (ETA and ETB). The prostatic tissue sections were incubated in four different stock solutions containing the following: 0.1 nM. 125I-endothelin-1 (125I-ET-1) (total ET-1 binding); 0.1 nM. 125I-ET-1 and 100 nM. S6C (total ETA binding); 0.1 nM. 125I-ET-1 and 1 microM. BQ123 (total ETB binding); and 0.1 nM. 125I-ET-1 and 1 microM. ET-1 (nonspecific ET-1 binding). Nonspecific binding accounted for only 12 and 15% of total 125I-ET-1 binding in the stroma and glandular epithelium. Autoradiograms were quantitatively analyzed using a computerized image analysis system. Specific radioactive densities (nCi/mg.) were determined for the stromal and glandular epithelial elements of the prostate. The specific radioactive densities of ETA and ETB binding sites in the stroma were 7.57 +/- 0.65 and 2.98 +/- 0.81. The specific radioactive densities of ETA and ETB binding sites in the glandular epithelium were 1.59 +/- 0.15 and 7.87 +/- 1.35. The present study demonstrates that the predominant endothelin receptors in the stroma and glandular epithelium are the ETA and ETB subtypes, respectively.The Journal of Urology 04/1994; 151(3):763-6. · 3.70 Impact Factor
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ABSTRACT: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m(2) was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.Investigational New Drugs 03/2007; 25(1):41-8. · 3.50 Impact Factor