Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine
| Autor: | C E Myers, M Castillo, P. L. De Souza |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Paclitaxel Transplantation Heterologous Pharmacology Mice chemistry.chemical_compound DU145 In vivo Internal medicine Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Animals Humans Lovastatin Viability assay Dose-Response Relationship Drug Oncogene business.industry Prostatic Neoplasms Drug Synergism Genes ras Endocrinology Oncology chemistry Quinacrine Cell culture Apoptosis Cancer cell business Neoplasm Transplantation Research Article |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 1106-1111 |
| Popis: | Cytoplasmic phospholipase A2 (PLA2) is known to be phosphorylated and activated by MAP kinase (Lin et al 1993, Cell 72: 269-278), an important downstream component of signal transduction, whereas paclitaxel has been shown to inhibit isoprenylation of ras proteins (Danesi et al 1995, Mol Pharmacol 47: 1106-1111). Given that quinacrine (Q), a PLA2 inhibitor, and paclitaxel (P) might act at different sites in the cell signalling pathway, our aim was to test whether they were synergistic in combination against prostate cancer cells. Cell viability of PC-3, PC-3M and DU145 cells in 96 - well plates was assessed 96 h after drugs were added concurrently. Using Chou analysis, we demonstrated synergy for the combination against all three cell lines. Further, synergy was present under both conservative (mutually non-exclusive) and non-conservative (mutually exclusive) models. Studies in the nude mouse xenograft model support the finding of synergy in vitro. In DU145-bearing mice, Q (50 mg kg(-1)) and P (0.5 mg kg(-1)) given daily for 12 consecutive days, either concurrently or sequentially, was more effective than either drug alone, at twice the dose intensity. In an enzyme-linked immunosorbent (ELISA) apoptosis assay, arachidonic acid was able to partially reverse Q- and P-induced apoptosis, suggesting PLA2 pathway involvement. Finally, the combination of lovastatin, another inhibitor of ras isoprenylation, and quinacrine had synergistic inhibitory effects on the growth of PC-3 cells in vitro, suggesting that the combination of these two classes of compounds might serve as an attractive therapeutic approach for prostate cancer. Images Figure 4 |
| Databáze: | OpenAIRE |
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