Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce General Hospital, Cuneo, Italy.
Urol Oncol. 2013 Aug;31(6):776-86. doi: 10.1016/j.urolonc.2011.03.018. Epub 2011 Jul 27.
To examine the anti-proliferative effect of the combination of docetaxel, the cornerstone of modern chemotherapy for prostate cancer, and vandetanib, a potent inhibitor of VEGFR-2 tyrosine kinase, applied to the representative hormone-refractory human prostate cancer cell line PC3. The aim is to analyze if a supra-additive/synergic effect of the combined treatment on cell viability exists and to understand the molecular key-factors involved. We first hypothesized an effect of vandetanib in modulation the function of MDR1, leading to a longer retention of docetaxel inside the cell. It may also be possible that vandetanib could modulate the docetaxel-induced changes in expression of prosurvival and proapoptotic proteins, leading to a positive balance forward cell death.
We used PC3 cells either wild type (PC3wt) or with acquired resistance to docetaxel (PC3R), characterized by a higher expression of MDR1. We studied both mRNA and protein, the expression of EGF and VEGF receptors at a basal level and after each treatment, as well as the expression of cell cycle and apoptosis related genes.
Cell proliferation data suggested a supra-additive cytotoxic effect of the combination of docetaxel plus vandetanib, when given together or with the sequence vandetanib followed by docetaxel. We did not observe any effect of vandetanib on MDR1, in the PC3R cell lines, characterized by a higher pump expression than PC3wt. On the other side, we defined a number of key factors involved in the pro- and anti-survival balance, which regulation, by single drugs and/or by combined treatment, could explain the effect on cell cytotoxicity; also where there are apparently contradictory results.
Our data suggest that combined treatment with vandetanib and docetaxel alters the balance of proapoptotic and prosurvival proteins, ultimately leading to potentiation of docetaxel-induced apoptosis in human prostate cancer cells in vitro, irrespective of cells being sensitive or resistant to docetaxel.
研究多西紫杉醇（现代前列腺癌化疗基石）与血管内皮生长因子受体-2（VEGFR-2）酪氨酸激酶强效抑制剂凡德他尼联合应用对代表性激素难治性人前列腺癌细胞系 PC3 的抗增殖作用。旨在分析联合治疗对细胞活力是否存在超加性/协同作用，并了解相关的分子关键因素。我们首先假设凡德他尼能够调节 MDR1 的功能，从而使多西紫杉醇在细胞内的滞留时间更长。也可能是凡德他尼能够调节多西紫杉醇诱导的存活和促凋亡蛋白表达的变化，导致细胞死亡的正向平衡。
我们使用野生型 PC3 细胞（PC3wt）或获得多西紫杉醇耐药的 PC3 细胞（PC3R）进行研究，PC3R 细胞的 MDR1 表达更高。我们在基础水平和每种治疗后研究了 EGF 和 VEGF 受体的 mRNA 和蛋白表达，以及细胞周期和凋亡相关基因的表达。
细胞增殖数据表明，多西紫杉醇联合凡德他尼联合应用具有超加性细胞毒性作用，无论是同时给予还是先给予凡德他尼后给予多西紫杉醇。我们在 MDR1 泵表达高于 PC3wt 的 PC3R 细胞系中未观察到凡德他尼对其的任何影响。另一方面，我们确定了一些涉及促生存和抗生存平衡的关键因素，这些因素的调节，无论是通过单一药物还是联合治疗，都可以解释对细胞细胞毒性的影响；并且在某些情况下，结果是矛盾的。
我们的数据表明，凡德他尼与多西紫杉醇联合治疗改变了促凋亡和促存活蛋白的平衡，最终导致体外人前列腺癌细胞中多西紫杉醇诱导的细胞凋亡增强，而与细胞对多西紫杉醇的敏感性或耐药性无关。
