Bonham Michael J, Galkin Anna, Montgomery Bruce, Stahl William L, Agus David, Nelson Peter S
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
J Natl Cancer Inst. 2002 Nov 6;94(21):1641-7. doi: 10.1093/jnci/94.21.1641.
PC-SPES is a botanical preparation shown to have efficacy in patients with androgen-dependent and androgen-independent prostate carcinoma. Several herbal constituents in PC-SPES inhibit tumor growth through cell cycle arrest and apoptosis, although the mechanisms of these activities are poorly defined. We sought to identify PC-SPES-induced changes in gene expression, specifically in those genes encoding cytoskeletal proteins that could be associated with PC-SPES-induced cytoxicity.
LNCaP prostate carcinoma cells were treated with PC-SPES, and changes in gene expression were determined by complementary DNA (cDNA) microarray hybridization and northern blot analyses. PC-SPES and paclitaxel, a microtubule-stabilizing drug, effects on microtubules were assessed by immunofluorescence of treated cells and by in vitro tubulin polymerization assays. In vivo effects of PC-SPES and paclitaxel were assessed using CWR22R androgen-independent prostate cancer xenografts. All statistical tests were two-sided.
PC-SPES treatment of LNCaP cells for 24 hours altered the expression of 17 cytoskeletal genes. mRNA levels of alpha-tubulin decreased sevenfold. Although paclitaxel stabilized and PC-SPES treatment disrupted microtubule architecture in LNCaP cells, the combination of both agents had an intermediate effect. PC-SPES inhibited tubulin polymerization in vitro, even in the presence of paclitaxel. Compared with tumors in control mice (mean tumor volume = 2983 mm(3), 95% confidence interval [CI] = 2380 to 3586 mm(3)), tumors were statistically significantly smaller in mice that received PC-SPES (mean tumor volume = 2018 mm(3), 95% CI = 1450 to 2568 mm(3); P =.028), paclitaxel (mean tumor volume = 1340 mm(3), 95% CI = 697 to 1983 mm(3); P<.001), or the combination of PC-SPES and paclitaxel (mean tumor volume = 1955 mm(3), 95% CI = 1260 to 2650 mm(3); P =.034).
PC-SPES may interfere with microtubule polymerization. This activity has implications for the clinical management of patients with advanced prostate cancer who may be taking PC-SPES concurrently with microtubule-modulating chemotherapeutic agents, such as paclitaxel.
PC-SPES是一种植物制剂，已证明对雄激素依赖性和非雄激素依赖性前列腺癌患者有效。PC-SPES中的几种草药成分通过细胞周期阻滞和凋亡来抑制肿瘤生长，尽管这些活性的机制尚不清楚。我们试图确定PC-SPES诱导的基因表达变化，特别是那些编码细胞骨架蛋白的基因，这些基因可能与PC-SPES诱导的细胞毒性有关。
用PC-SPES处理LNCaP前列腺癌细胞，通过互补DNA（cDNA）微阵列杂交和Northern印迹分析确定基因表达的变化。通过对处理过的细胞进行免疫荧光和体外微管蛋白聚合试验，评估PC-SPES和紫杉醇（一种微管稳定药物）对微管的影响。使用CWR22R非雄激素依赖性前列腺癌异种移植物评估PC-SPES和紫杉醇的体内作用。所有统计检验均为双侧检验。
用PC-SPES处理LNCaP细胞24小时后，17个细胞骨架基因的表达发生改变。α-微管蛋白的mRNA水平下降了7倍。虽然紫杉醇使LNCaP细胞中的微管结构稳定，而PC-SPES处理则破坏微管结构，但两种药物联合使用具有中间效应。即使在存在紫杉醇的情况下，PC-SPES在体外也能抑制微管蛋白聚合。与对照小鼠的肿瘤（平均肿瘤体积=2983mm³，95%置信区间[CI]=2380至3586mm³）相比，接受PC-SPES（平均肿瘤体积=2018mm³，95%CI=1450至2568mm³；P=0.028）、紫杉醇（平均肿瘤体积=1340mm³，95%CI=697至1983mm³；P<0.001）或PC-SPES与紫杉醇联合使用（平均肿瘤体积=1955mm³，95%CI=1260至2650mm³；P=0.034）的小鼠的肿瘤在统计学上显著更小。
PC-SPES可能会干扰微管蛋白聚合。这一活性对于可能同时服用PC-SPES和微管调节化疗药物（如紫杉醇）的晚期前列腺癌患者的临床管理具有重要意义。
