Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street, London, ON, N6A 3K7, Canada.
Department of Medical Biophysics, The University of Western Ontario, London, ON, N6A 3K7, Canada.
J Neurooncol. 2018 Jan;136(2):255-262. doi: 10.1007/s11060-017-2664-9. Epub 2017 Nov 16.
Intracellular pH (pH) plays an important role in the maintenance of normal cell function, and is maintained within a narrow range by the activity of transporters located at the plasma membrane. Modulation of tumor pH may influence proliferation, apoptosis, chemotherapy resistance, and thermosensitivity. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on cellular pH. Amine and amide concentration-independent detection (AACID) is a recently developed CEST contrast method that is intracellular pH (pH) weighted. Dichloroacetate (DCA) can alter tumor pH by inhibiting the enzyme pyruvate dehydrogenase kinase causing reduced lactate (increasing pH), or by decreasing the expression of monocarboxylate transporters and vacuolar ATPase leading to reduced pH. Since the net in vivo effect of DCA on pH is difficult to predict, the purpose of this study was to quantify the magnitude of acute pH change in glioblastoma after a single DCA injection using AACID CEST MRI. Using a 9.4T MRI scanner, CEST spectra were acquired in six mice approximately 14 days after implanting 10 U87 human glioblastoma multiforme (GBM) cells in the brain, before and after intravenous injection of DCA (dose: 200 mg/kg). Three additional mice received only phosphate buffered saline (PBS) injection and were studied as controls. Repeated measures t test was used to compare AACID changes in tumor and contralateral tissue regions of interest. One hour after DCA injection there was a significant increase in tumor AACID level by 0.04 ± 0.01 corresponding to a 0.16 decrease in pH, and no change in AACID in contralateral tissue. Inspection of AACID maps following PBS injection showed no differences. The use of DCA to induce a tumor specific pH change detectable by AACID CEST MRI is consistent with previous studies that have shown similar effects for lonidamine and topiramate. This study demonstrates that a single dose of DCA can be used as a pharmacological challenge to induced rapid tumor intracellular acidification.
细胞内 pH（pH）在维持正常细胞功能方面起着重要作用，其通过位于质膜上的转运蛋白的活性维持在一个狭窄的范围内。肿瘤 pH 的调节可能会影响增殖、凋亡、化疗耐药性和热敏性。化学交换饱和转移（CEST）是一种新的 MRI 对比机制，依赖于细胞内 pH。最近开发的一种 CEST 对比方法，即胺和酰胺浓度无关检测（AACID），是 pH 加权的。二氯乙酸（DCA）可以通过抑制丙酮酸脱氢酶激酶来改变肿瘤 pH，导致乳酸减少（增加 pH），或者通过降低单羧酸转运蛋白和液泡型 ATP 酶的表达来减少 pH。由于 DCA 对 pH 的体内净影响难以预测，因此本研究旨在使用 AACID CEST MRI 定量测量单次 DCA 注射后脑内胶质母细胞瘤（GBM）的急性 pH 变化幅度。使用 9.4T MRI 扫描仪，在脑内植入 10 U87 人胶质母细胞瘤后约 14 天，在静脉注射 DCA（剂量：200 mg/kg）前后，对 6 只小鼠进行 CEST 光谱采集。另外 3 只只接受磷酸盐缓冲盐水（PBS）注射作为对照进行研究。采用重复测量 t 检验比较肿瘤和对侧组织感兴趣区的 AACID 变化。DCA 注射后 1 小时，肿瘤 AACID 水平显著增加 0.04 ± 0.01，对应 pH 降低 0.16，对侧组织的 AACID 无变化。对 PBS 注射后 AACID 图谱的检查显示无差异。使用 DCA 诱导可通过 AACID CEST MRI 检测的肿瘤特异性 pH 变化与先前研究一致，这些研究表明 lonidamine 和 topiramate 具有类似的效果。本研究表明，单次 DCA 剂量可作为一种药理学挑战，诱导快速肿瘤细胞内酸化。
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