The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer
The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer
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DOI：
10.1080/02841860600996447
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发表时间：
2007-01-01
期刊：
影响因子：
3.1
通讯作者：
Leonard, Robert C. F.
中科院分区：
文献类型：
--
作者：
Morgan, Claire;Lewis, Paul D.;Leonard, Robert C. F.
双膦酸盐和化疗在转移性激素抵抗性前列腺癌的治疗中越来越受到青睐。我们研究了唑来膦酸，在骨中发现的浓度，是否会增强多西他赛在激素抵抗前列腺癌细胞系PC-3中的抗肿瘤活性。将细胞暴露于与多西他赛（3 nM）组合或依次的唑来膦酸（1 mM）。在药物处理后48或72小时分析细胞活力、细胞凋亡和甲羟戊酸途径抑制的标志物。细胞活力的降低和细胞凋亡水平的增加在唑来膦酸单药治疗中最为明显。蛋白质印迹分析显示，所有药物治疗的增殖标志物微型染色体维持蛋白2（MCM 2）的总体降低和半胱天冬酶-3前体的降低，以及使用单一药剂唑来膦酸和唑来膦酸-多西他赛序列的Rho A水平的显著降低。这项研究强调了唑来膦酸的效力，当使用浓度与骨中发现的浓度相似时，会降低细胞活力并引起细胞凋亡。临床上，这些发现表明，在由于激素抵抗性前列腺癌导致骨转移的患者中，这些患者不适合全身化疗，单药唑来膦酸可能对前列腺癌上皮细胞的活力有直接影响。
Bisphosphonates and chemotherapy have increasingly gained favour in the treatment of metastatic hormone resistant prostate cancer. We investigated whether zoledronic acid, at a concentration found at the bone, would enhance the antitumour activity of docetaxel in the hormone resistant prostate cancer cell line PC-3. Cells were exposed to zoledronic acid (1 mM) in combination or in sequence with docetaxel (3 nM). Cell viability, apoptosis and markers for inhibition of the mevalonate pathway were analyzed 48 or 72 hours after drug treatment. Reduction in cell viability and increased apoptosis levels were most pronounced with single agent zoledronic acid. Western blot analysis showed an overall reduction in the proliferation marker Mini chromosome maintenance protein 2 (MCM2) and reduction in caspase-3 precursor for all drug treatments and a marked reduction in Rho A levels with single agent zoledronic acid and zoledronic acid-docetaxel sequence. This study highlights the potency of zoledronic acid, when used at concentrations similar to those found at the bone, in reducing cell viability and causing apoptosis. Clinically, these findings suggest that in patients with bone metastases due to hormone resistance prostate cancer, who are not fit enough for systemic chemotherapy, single agent zoledronic acid may have a direct effect on viability of prostate cancer epithelial cells.