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Induction of apoptosis in malignant and camptothecin-resistant human cells
D Chatterjee1, J H Wyche, P Pantazis
1Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.
Abstract:
Flow cytometry studies demonstrate that androgen-independent human prostate carcinoma DU-145 cells are arrested at the G1-phase of the cell cycle in the presence of suramin, but they die by apoptosis in the presence of 9-nitrocamptothecin (9NC). The addition of cytostatic concentrations of suramin increases the apoptotic action of 9NC on DU-145 cells, and induces apoptosis in 9NC-resistant DU-145/RC cells that were derived from the parental DU-145 cells by continuous exposure to progressively increased concentrations of 9NC. In addition, the topoisomerase II-directed drug etoposide exerts more extensive apoptotic action on DU-145/RC than DU-145 cells. Increased resistance of DU-145 cells to 9 NC and collaterally increased sensitivity to etoposide and suramin appear to correlate with alterations in the structure rather than synthesis of topoisomerases and possibly with specific cellular proteins that regulate apoptosis. The results suggest that etoposide and suramin may be successful alternative treatments for 9NC-resistant androgen-independent prostate cancer.
Insights
Suramin enhances 9-nitrocamptothecin (9NC) cancer cell death and induces apoptosis in 9NC-resistant cells. Etoposide and suramin show promise for treating 9NC-resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen-independent prostate cancer is challenging to treat.
- Drug resistance, particularly to 9-nitrocamptothecin (9NC), limits therapeutic options.
- Understanding mechanisms of drug resistance and identifying alternative treatments are crucial.
Purpose of the Study:
- To investigate the synergistic effects of suramin and 9NC on prostate cancer cells.
- To explore the efficacy of suramin and etoposide in 9NC-resistant prostate cancer models.
- To correlate drug resistance with alterations in topoisomerases and apoptosis-regulating proteins.
Main Methods:
- Flow cytometry was used to analyze cell cycle arrest and apoptosis.
- DU-145 (prostate carcinoma) and DU-145/RC (9NC-resistant) cell lines were utilized.
- Treatment with suramin, 9-nitrocamptothecin (9NC), and etoposide was administered.
Main Results:
- Suramin caused G1-phase cell cycle arrest in DU-145 cells and induced apoptosis.
- Suramin enhanced the apoptotic effect of 9NC on DU-145 cells.
- Suramin induced apoptosis in 9NC-resistant DU-145/RC cells, and etoposide showed greater efficacy on these cells.
- Drug resistance correlated with structural changes in topoisomerases and apoptosis-regulating proteins.
Conclusions:
- Suramin potentiates the apoptotic activity of 9NC and overcomes 9NC resistance in prostate cancer cells.
- Etoposide and suramin represent potential alternative therapeutic strategies for 9NC-resistant androgen-independent prostate cancer.