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Antitumor activity of a novel glyco-nitric oxide conjugate in ovarian carcinoma
G Cantuaria1, A Magalhaes, R Angioli
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Miami, Florida.
Background:
Several studies have shown that nitric oxide (NO)-releasing agents can kill tumor cells. Unfortunately, currently available NO delivery molecules do not target tumor cells preferentially. To exploit the overexpression of glucose transport proteins and the high level of glucose transport characteristics of tumor cells, glucose was conjugated to S-nitroso-N-acetyl-penicillamine (2-gluSNAP) and evaluated for cytotoxicity in human ovarian carcinoma cells.
Methods:
The cytotoxicity of 2-gluSNAP and SNAP was assessed by clonogenic cell survival assays performed in A2780S (cisplatin sensitive) and A2780cP (cisplatin-resistant) ovarian carcinoma cells in vitro. Immunoblotting and immunohistochemistry were used to assess the expression of Glut-1 hexose transport protein in the cell lines as well as in paraffin blocks from 28 surgical specimens of epithelial ovarian carcinoma. Apoptosis was assessed by an end-labeling assay.
Results:
The ovarian carcinoma cell lines consistently were more sensitive to 2-gluSNAP than SNAP alone. The median effective doses (MEDs) for 2-gluSNAP and SNAP in the A2780s cell line were 0.0042 microM and 20.4 microM, respectively. Therefore, 2-GluSNAP was nearly 5000-fold more potent than the NO-donating moiety (SNAP) alone. In the A2780cP cells, the MED for 2-gluSNAP (0.38 microM) was 250-fold lower than that for SNAP alone (100 microM). Immunoblotting and immunohistochemistry studies showed overexpression of Glut-1 in the cell lines and in 23 of 28 epithelial ovarian carcinoma specimens.
Conclusions:
The novel glyco-NO conjugate 2-gluSNAP exhibits a much greater cytotoxicity than the parent NO donor without the hexose moiety. These agents have the potential to target tumor cells preferentially, that overexpress Glut-1. This transporter is expressed highly in epithelial ovarian carcinoma.
Insights
A novel glucose-conjugated nitric oxide (NO) donor, 2-gluSNAP, shows significantly enhanced cancer cell killing. This targeted approach exploits high glucose transporter (Glut-1) expression in ovarian tumors for improved efficacy.
Area of Science:
- Biochemistry
- Oncology
- Drug Delivery
Background:
- Nitric oxide (NO)-releasing agents demonstrate tumor cell cytotoxicity.
- Current NO delivery lacks tumor-specific targeting.
- Exploiting tumor cell glucose metabolism offers a potential targeting strategy.
Purpose of the Study:
- To synthesize and evaluate a novel glucose-conjugated NO donor (2-gluSNAP) for targeted ovarian cancer therapy.
- To assess the cytotoxicity of 2-gluSNAP in human ovarian carcinoma cells.
- To investigate the role of glucose transporter 1 (Glut-1) in mediating the efficacy of 2-gluSNAP.
Main Methods:
- Cytotoxicity assessed via clonogenic cell survival assays in ovarian cancer cell lines (A2780S, A2780cP).
- Glut-1 expression analyzed using immunoblotting and immunohistochemistry in cell lines and patient specimens.
- Apoptosis was evaluated using an end-labeling assay.
Main Results:
- 2-gluSNAP exhibited significantly higher potency than SNAP alone in both cisplatin-sensitive and resistant ovarian cancer cells.
- 2-gluSNAP was up to 5000-fold more potent than SNAP in A2780s cells.
- Overexpression of Glut-1 was confirmed in ovarian cancer cell lines and a majority of epithelial ovarian carcinoma specimens.
Conclusions:
- The novel glyco-NO conjugate 2-gluSNAP demonstrates superior cytotoxicity compared to the parent NO donor.
- 2-gluSNAP has potential for preferential targeting of tumor cells overexpressing Glut-1.
- High Glut-1 expression in epithelial ovarian carcinoma supports the therapeutic potential of 2-gluSNAP.