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Inhibition of normal and experimental angiotumor endothelial cell proliferation and cell cycle progression by
1Department of Surgery, The University of Arizona, Tucson, Arizona 85724, USA. reiser@azstarnet.com
Abstract:
With rapid growth and metabolism, aggressive cancers require an extensive vascular network, termed tumor angiogenesis. The body produces a variety of natural angiogenic inhibitors, among which is the mammalian estrogen metabolite, 2-methoxyestradiol (2-MeOE2). In this study, we compared the effects of 2-MeOE2 on a human umbilical vein cell line (HUVEC-C) and on an immortal, angiotumor-producing rat sinusoidal endothelial cell line (RSE-1). In vitro, the effects of varying concentrations of 2-MeOE2 from 0.01-100.0 microM were measured with cell counts and compared to control cells. HUVEC-C had an ED50 approximately 3.5 microM with approximately 27% inhibition of cell growth whereas RSE-1 had an ED50 approximately 2.2 microM with approximately 50% inhibition of cell growth compared with controls. The lowest concentration with maximal effect was 10.0 microM 2-MeOE2 for both cell lines. Using this concentration, flow cytometric analysis of cell cycles was performed with propidium iodide stained DNA of HUVEC-C and RSE-1 at 24 and 48 hr. Both demonstrated a significant (P < 0.0001) block at G2M of the cell cycle. At 48 hr, HUVEC-C had 32% of cells in G2M (control = 9% G2M), and RSE-1 had 36% of cells in G2M (control = 18% G2M). These findings demonstrate a strong in vitro antiproliferative effect of 2-MeOE2 on normal dividing endothelial as well as angiotumor cells mediated through a cell cycle-specific block at G2M. The antiendothelial, antiangiotumor effect of 2-MeOE2 supports its potential as a therapeutic agent against solid organ cancers, benign or malignant vascular growths, and other pathologic states dependent on angiogenesis.
Insights
2-methoxyestradiol (2-MeOE2) effectively inhibits endothelial cell growth and tumor angiogenesis by blocking the cell cycle at G2M. This natural estrogen metabolite shows promise as an anti-cancer therapeutic agent.
Area of Science:
- Endocrinology
- Cell Biology
- Oncology
Background:
- Tumor angiogenesis is crucial for aggressive cancer growth.
- Natural angiogenic inhibitors, like 2-methoxyestradiol (2-MeOE2), offer therapeutic potential.
- 2-MeOE2 is a mammalian estrogen metabolite with known anti-angiogenic properties.
Purpose of the Study:
- To compare the in vitro anti-proliferative effects of 2-MeOE2 on normal endothelial cells and tumor-associated endothelial cells.
- To investigate the mechanism of action of 2-MeOE2 on endothelial cell cycle progression.
- To evaluate the potential of 2-MeOE2 as a therapeutic agent for angiogenesis-dependent diseases.
Main Methods:
- Utilized human umbilical vein endothelial cells (HUVEC-C) and rat sinusoidal endothelial cells (RSE-1).
- Assessed cell proliferation using cell counts at varying 2-MeOE2 concentrations (0.01-100.0 microM).
- Performed flow cytometric analysis of cell cycle distribution (G2M block) using propidium iodide staining at 24 and 48 hours.
Main Results:
- 2-MeOE2 demonstrated significant anti-proliferative effects on both HUVEC-C (ED50 ~3.5 microM, 27% inhibition) and RSE-1 (ED50 ~2.2 microM, 50% inhibition).
- Maximal inhibition was observed at 10.0 microM 2-MeOE2 for both cell lines.
- Flow cytometry revealed a significant G2M cell cycle block in both cell lines at 48 hours (HUVEC-C: 32%, RSE-1: 36%) compared to controls.
Conclusions:
- 2-MeOE2 exhibits a potent in vitro antiproliferative effect on endothelial and angiotumor cells.
- The anti-proliferative mechanism involves a specific cell cycle block at G2M.
- 2-MeOE2's anti-angiogenic properties support its potential as a therapeutic agent for various cancers and vascular disorders.