Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine

Abstract

Summary 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 Pharmacol47: 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 nonexclusive) 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-') and P (0.5 mg kg-') 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.

Effects of 12-O-Tetradecanoylphorbol-13-acetate (TPA) in Combination with Paclitaxel (Taxol) on Prostate Cancer LNCaP Cells Cultured In vitro or Grown as Xenograft Tumors in Immunodeficient Mice

“…Because treatment with paclitaxel is associated with significant toxic side effects that limit its dose and duration of use (14 -18), efforts have been devoted to develop effective combinations of paclitaxel with other anticancer agents. Earlier studies have shown that combinations of paclitaxel and 1a,25-dihydroxyvitamin D 3 (26) or paclitaxel and quinacrine (27) enhanced the anticancer activity of paclitaxel. The present study showed that very low concentrations of paclitaxel in combination with TPA synergistically inhibited the growth and increased apoptosis in LNCaP prostate cancer cells.…”

Quinacrine synergizes with 5-fluorouracil and other therapies in colorectal cancer

“…10 It has also been shown that quinacrine can synergize with chemotherapy in a variety of other systems. 26,27 Given its broad spectrum of activity, we thus hypothesized that quinacrine could enhance, if not synergize, with both conventional chemotherapeutic agents and targeted therapies in colorectal cancer. A preliminary screen with RKO cells showed that indeed quinacrine could enhance the anticancer activity of many such agents (Fig.…”

MAP Kinases and Prostate Cancer

“…In different tumor cells, expression of some EGF family members such as EGF or TGF-α is associated with poor patient prognosis or resistance to chemotherapeutics [94][95][96][97][98][99]. IGF-1 and EGF stimulate intracellular signaling pathways converging at the level of ERK2 [100], which is a key kinase mediator of growth-factor-induced mitogenesis in prostate cancer cells [101]. The two major substrates of the IGF-1 receptor, insulin receptor substrate-1 [102] and Shc, are known to contribute to IGF-1-induced activation of ERK [103].…”