Department of Cancer Imaging Research, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, USA.
Clin Exp Metastasis. 2011 Dec;28(8):841-9. doi: 10.1007/s10585-011-9415-7. Epub 2011 Aug 23.
The tumor microenvironment is acidic as a consequence of upregulated glycolysis and poor perfusion and this acidity, in turn, promotes invasion and metastasis. We have recently demonstrated that chronic consumption of sodium bicarbonate increased tumor pH and reduced spontaneous and experimental metastases. This occurred without affecting systemic pH, which was compensated. Additionally, these prior data did not rule out the possibility that bicarbonate was working though effects on carbonic anhydrase, and not as a buffer per se. Here, we present evidence that chronic ingestion of a non-volatile buffer, 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA) with a pK (a) of 6.9 also reduced metastasis in an experimental PC3M prostate cancer mouse model. Animals (n = 30) were injected with luciferase expressing PC3M prostate cancer cells either subcutaneously (s.c., n = 10) or intravenously (i.v., n = 20). Four days prior to inoculations, half of the animals for each experiment were provided drinking water containing 200 mM IEPA buffer. Animals were imaged weekly to follow metastasis, and these data showed that animals treated with IEPA had significantly fewer experimental lung metastasis compared to control groups (P < 0.04). Consistent with prior work, the pH of treated tumors was elevated compared to controls. IEPA is observable by in vivo magnetic resonance spectroscopy and this was used to measure the presence of IEPA in the bladder, confirming that it was orally available. The results of this study indicate that metastasis can be reduced by non-volatile buffers as well as bicarbonate and thus the effect appears to be due to pH buffering per se.
肿瘤微环境呈酸性，这是由于糖酵解上调和灌注不良所致，这种酸度反过来又促进了侵袭和转移。我们最近的研究表明，慢性碳酸氢钠的消耗会增加肿瘤的 pH 值并减少自发性和实验性转移。这是在不影响系统 pH 值的情况下发生的，系统 pH 值得到了代偿。此外，这些先前的数据并未排除碳酸氢盐可能通过碳酸酐酶的作用而不是作为缓冲剂本身起作用的可能性。在这里，我们提供了证据表明，慢性摄入非挥发性缓冲剂 2-咪唑-1-基-3-乙氧羰基丙酸（IEPA），其 pK（a）为 6.9，也可以降低实验性 PC3M 前列腺癌小鼠模型中的转移。将表达荧光素酶的 PC3M 前列腺癌细胞皮下（s.c.，n=10）或静脉内（i.v.，n=20）注射到动物（n=30）中。在接种前 4 天，每个实验的一半动物提供含有 200 mM IEPA 缓冲液的饮用水。每周对动物进行成像以跟踪转移，这些数据表明，与对照组相比，用 IEPA 治疗的动物的实验性肺转移明显减少（P<0.04）。与先前的工作一致，处理过的肿瘤的 pH 值比对照升高。IEPA 可通过体内磁共振波谱进行观察，并用其测量膀胱中 IEPA 的存在，以确认其可口服使用。这项研究的结果表明，非挥发性缓冲剂以及碳酸氢盐可以减少转移，因此，这种作用似乎是由于 pH 缓冲本身所致。
