Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of a novel histone deacetylase inhibitor, LAQ824, in human colon carcinoma cells and xenografts
Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of a novel histone deacetylase inhibitor, LAQ824, in human colon carcinoma cells and xenografts
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DOI：
10.1593/neo.07834
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Beloueche-Babari, Mounia
中科院分区：
文献类型：
--
作者：
Chung, Yuen-Li;Troy, Helen;Beloueche-Babari, Mounia
利用磷磁共振波谱技术（P-31 MRS）研究了组蛋白去乙酰化酶（HDAC）抑制剂LAQ824的药效学作用。用LAQ824和另一种HDAC抑制剂亚甲基苯胺羟肟酸治疗HT29结肠癌细胞后，用31P MRS检测HT29结肠癌细胞。采用P-31 MRS检测HT29异种移植物和肿瘤提取物，以及laq824处理前后。Western blot检测组蛋白H3乙酰化程度，CD31免疫组化染色检测肿瘤微血管密度。LAQ824和亚甲基苯胺羟肟酸处理后，HT29细胞中磷胆碱含量显著升高。在体内，laq824处理的HT29异种移植物中，磷同酯/总磷（TotP）信号的比值显著升高，且该比值与肿瘤体积的变化呈负相关。在laq824治疗的肿瘤中，细胞内pH、β -三磷酸核苷(β - ntp)/TotP和β - ntp /无机磷酸盐（Pi）也有统计学意义的降低，Pi/TotP也有统计学意义的增加。LAQ824处理后，肿瘤提取物显示出许多显著的代谢变化，同时组蛋白乙酰化升高，微血管密度降低。LAQ824治疗导致磷脂代谢改变和肿瘤生物能量学受损。在LAQ824或其他HDAC抑制剂治疗后，磷酸胆碱和磷酸单酯的增加可能有潜力作为无创监测肿瘤反应的药效学标志物。
The aim of this work was to use phosphorus magnetic resonance spectroscopy (P-31 MRS) to investigate the pharmacodynamic effects of LAQ824, a histone deacetylase (HDAC) inhibitor. Human HT29 colon carcinoma cells were examined by 31P MRS after treatment with LAQ824 and another HDAC inhibitor, suberoylanilide hydroxamic acid. HT29 xenografts and tumor extracts were also examined using P-31 MRS, pre- and post-LAQ824 treatment. Histone H3 acetylation was determined using Western blot analysis, and tumor microvessel density by immunohistochemical staining of CD31. Phosphocholine showed a significant increase in HT29 cells after treatment with LAQ824 and suberoylanilide hydroxamic acid. In vivo, the ratio of phosphomonoester/total phosphorus (TotP) signal was significantly increased in LAQ824-treated HT29 xenografts, and this ratio was inversely correlated with changes in tumor volume. Statistically significant decreases in intracellular pH, beta-nucleoside triphosphate (beta-NTP)/TotP, and beta-NTP/inorganic phosphate (Pi) and an increase in Pi/TotP were also seen in LAQ824-treated tumors. Tumor extracts showed many significant metabolic changes after LAQ824 treatment, in parallel with increased histone acetylation and decreased microvessel density. Treatment with LAQ824 resulted in altered phospholipid metabolism and compromised tumor bioenergetics. The phosphocholine and phosphomonoester increases may have the potential to act as pharmacodynamic markers for noninvasively monitoring tumor response after treatment with LAQ824 or other HDAC inhibitors.