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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
Novel small molecule alpha v integrin antagonists: comparative anti-cancer efficacy with known angiogenesis
J S Kerr1, R S Wexler, S A Mousa
1DuPont Pharmaceuticals Co., Wilmington, DE 19880-0400, USA. Janet.S.Kerr@dupontpharma.com
Abstract:
Recent evidence supports the involvement of integrins in angiogenesis: blockade of alpha v beta 3 and alpha v beta 5 integrins disrupts angiogenesis leading to decreased blood vessel formation and hence decreased tumor growth. We hypothesized that av antagonists could inhibit tumor growth in tumor cells devoid of alpha v beta 3 integrins. We evaluated SM256 and SD983, novel small molecules that are specific av antagonists in mouse models of angiogenesis and tumorigenesis, and compared them with standards: TNP470, a fumagillin analog in the clinic, and flavopiridol, a cell cycle kinase inhibitor. In vitro SM256 was a selective alpha v beta 3 inhibitor with an IC50 = 4nM, and the affinity of SD983 against the mouse endothelial alpha v beta 3 integrin yielded an IC50 = 2nM and an IC50 = 54nM against alpha v beta 5. In the mouse Matrigel model of angiogenesis SM256 decreased blood vessel formation (hemoglobin content) with an ED50 = 0.055 ug/kg/day, tenfold more potent than TNP470. SG545, an ester of SD983, decreased blood vessel formation with an ED50 = 6 ug/kg/day, while flavopiridol ED50 = 18 ug/kg/day. In the mouse xenograft model, using human colon carcinoma RKO cells that do not express alpha v beta 3 but express alpha v beta 5, tumor growth was inhibited by SG545 (10 mg/kg/day) and flavopiridol (5 mg/kg/every other day) 40% and 70%, respectively (p < 0.05). Although the proliferative index (measured by BrdU incorporation) was not significantly changed with SM256, SG545 or flavopiridol (29-32%), the apoptotic index increased significantly (p < 0.05) in the SM256 and SG545-treated groups (2.3-2.7%) compared with controls (1.1%), suggesting increased cell death contributed to decreased tumor volumes. Neovascularization decreased with SM256 and SG545 treatment. The data demonstrate that potent selective av antagonist can target endothelial cells, tumor cells, inhibit angiogenesis and inhibit tumor growth.
Insights
Novel integrin alpha v antagonists, SM256 and SD983, effectively inhibit tumor growth by blocking angiogenesis and promoting apoptosis in preclinical models. These small molecules show potent anti-tumorigenic effects, offering new therapeutic strategies.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Integrins, specifically alpha v beta 3 and alpha v beta 5, play a crucial role in angiogenesis, the formation of new blood vessels.
- Blocking these integrins has shown promise in reducing tumor growth by inhibiting angiogenesis.
Purpose of the Study:
- To evaluate the efficacy of novel small molecule alpha v integrin antagonists, SM256 and SD983, in inhibiting tumor growth and angiogenesis.
- To compare the anti-angiogenic and anti-tumorigenic effects of these novel compounds with established agents like TNP470 and flavopiridol.
Main Methods:
- In vitro assessment of integrin inhibition using IC50 values.
- In vivo evaluation in mouse Matrigel models for angiogenesis and mouse xenograft models for tumor growth.
- Analysis of cell proliferation (BrdU incorporation) and apoptosis (apoptotic index).
Main Results:
- SM256 demonstrated potent inhibition of angiogenesis in the Matrigel model, outperforming TNP470.
- SG545 (an ester of SD983) and flavopiridol significantly inhibited tumor growth in a human colon carcinoma xenograft model.
- Treatment with SM256 and SG545 led to increased apoptosis and decreased neovascularization, suggesting cell death as a key mechanism.
Conclusions:
- Potent and selective alpha v integrin antagonists can effectively inhibit angiogenesis and tumor growth.
- These novel small molecules represent promising therapeutic candidates for cancer treatment.
- Targeting endothelial and tumor cells via integrin antagonism offers a viable strategy for anti-cancer drug development.
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