Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine.
Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine.
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DOI：
10.1038/bjc.1997.272
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发表时间：
1997
影响因子：
8.8
通讯作者：
Myers, CE
中科院分区：
文献类型：
--
作者：
deSouza, PL;Castillo, M;Myers, CE
已知细胞质磷脂酶A2（PLA 2）被MAP激酶磷酸化和活化（Lin等1993，Cell 72：269-278），MAP激酶是信号转导的重要下游组分，而紫杉醇已显示抑制ras蛋白的异戊二烯化（Danesi等1995，Mol Pharmacol 47：1106-1111）。考虑到PLA 2抑制剂奎纳克林（Q）和紫杉醇（P）可能作用于细胞信号传导途径中的不同位点，我们的目的是测试它们组合是否对前列腺癌细胞具有协同作用。在同时加入药物后96小时评估96孔板中PC-3、PC-3 M和DU 145细胞的细胞活力。使用Chou分析，我们证明了组合对所有三种细胞系的协同作用。此外，在保守（互不排斥）和非保守（互不排斥）模型下均存在协同作用。在裸鼠异种移植模型中的研究支持体外协同作用的发现。在DU 145荷瘤小鼠中，Q（50 mg kg（-1））和P（0.5 mg kg（-1））每日同时或顺序给药，连续12天，比单用任何一种药物更有效，剂量强度为2倍。在酶联免疫吸附（ELISA）细胞凋亡测定，花生四烯酸能够部分逆转Q-和P-诱导的细胞凋亡，表明PLA 2途径参与。最后，另一种ras异戊二烯化抑制剂洛伐他汀和奎纳克林的组合对体外PC-3细胞的生长具有协同抑制作用，表明这两类化合物的组合可能作为前列腺癌的有吸引力的治疗方法。
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.
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影响因子：
3.5
作者：
HANADA, K;KINOSHITA, E;SUGIYAMA, M
通讯作者：
SUGIYAMA, M
影响因子：
4.2
作者：
BABB, RR
通讯作者：
BABB, RR
影响因子：
4.6
作者：
RUCH, RJ;MADHUKAR, BV;KLAUNIG, JE
通讯作者：
KLAUNIG, JE
DOI：
10.1083/jcb.117.2.347
发表时间：
1992-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fenton RG;Kung HF;Longo DL;Smith MR
通讯作者：
Smith MR
影响因子：
3
作者：
EISEMAN, JL;EDDINGTON, ND;EGORIN, MJ
通讯作者：
EGORIN, MJ