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Enhancement of Cisplatin Sensitivity of Cisplatin-Resistant Human Cervical Carcinoma Cells by Bryostatin 1

Authors' Affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas

Requests for reprints: Alakananda Basu, Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107. Phone: 817-735-2487; Fax: 817-735-2118; E-mail: abasu{at}hsc.unt.edu.

Purpose: Bryostatin 1, a unique protein kinase C (PKC) activator, is already in the clinical trials. An understanding of complex regulation of PKC by bryostatin 1 is essential for effective use of bryostatin 1 in the clinic. We have previously shown that the ability of bryostatin 1 to enhance cisplatin sensitivity correlated with its ability to down-regulate PKC in HeLa cells. We have investigated how bryostatin 1 influences PKC regulation in cisplatin-resistant HeLa (HeLa/CP) cells, and if bryostatin 1 could be used to reverse cisplatin resistance.

Experimental Design: Phorbol 12,13-dibutyrate (PDBu), bryostatin 1, and small interfering RNA were used to manipulate PKC level/activation status. Cell death was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Annexin V dye-binding assay, and analysis of hypodiploid peak in a flow cytometer.

Results: Bryostatin 1 elicited a biphasic concentration response on PKC down-regulation and cisplatin-induced cell death in HeLa/CP cells; the maximum effect was achieved with 1 nmol/L bryostatin 1. Down-regulation of PKC increased with increasing concentrations of bryostatin 1. PDBu induced down-regulation of PKC in HeLa and HeLa/CP cells but it had little effect on PKC down-regulation in HeLa/CP cells. However, both PDBu and bryostatin 1 enhanced the sensitivity of HeLa/CP cells to cisplatin. Knockdown of PKC by small interfering RNA inhibited cisplatin-induced apoptosis but knockdown of PKC enhanced cisplatin-induced cell death.

Conclusions: These results suggest that although PKC acts as a proapoptotic protein, full-length PKC may inhibit cisplatin-induced cell death. Thus, persistent activation/down-regulation of PKC by bryostatin 1 was associated with cisplatin sensitization. Furthermore, PKC acts as an antiapoptotic protein and down-regulation of PKC by PDBu was associated with cellular sensitization to cisplatin.

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