Bicarbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer.
Bicarbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer.
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DOI：
10.1186/1471-2407-11-235
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发表时间：
2011-06-10
期刊：
影响因子：
3.8
通讯作者：
Martin NK
中科院分区：
文献类型：
--
作者：
Robey IF;Martin NK
恶性肿瘤的糖酵解特性导致肿瘤微环境中细胞外酸度较高。肿瘤酸性是肿瘤侵袭和转移的驱动因素。最近，研究表明，通过全身口服碳酸氢盐缓冲细胞外酸度可以抑制转移性乳腺癌小鼠模型中的转移扩散。虽然这些发现令人信服，但最近对使用口服碳酸氢盐作为癌症干预措施的评估显示其局限性。我们假设碳酸氢盐的安全性和有效性可以通过二氯乙酸（DCA）来增强，二氯乙酸是一种选择性靶向肿瘤细胞并通过抑制糖酵解来降低细胞外酸度的药物。使用我们的转移性乳腺癌小鼠模型（MDA-MB-231），我们设计了一项介入性生存研究，在该研究中，荷瘤小鼠长期接受碳酸氢盐、DCA或DCA-碳酸氢盐（DB）治疗。单独使用二氯乙酸或与碳酸氢盐联合使用均不会增加小鼠全身碱中毒。给予碳酸氢盐为基础的治疗的小鼠存活时间最长。手术后原发肿瘤的复发与生存率有关。虽然DB治疗没有显著增强口服碳酸氢钠，但我们确实观察到该队列中肺病变直径减小。DCA单药治疗在减小肿瘤大小或转移或改善生存时间方面无效。我们提供的体外证据表明，这种结果可能是肿瘤微环境缺氧的一个功能。DB联合治疗似乎没有增强慢性口服碳酸氢盐的效果。DCA的抗肿瘤作用可能与肿瘤模型有关。我们的研究表明，DCA作为一种癌症治疗方法的疗效是不可预测的，需要进一步的研究来确定该药物在肿瘤微环境中的作用。
The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations. We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically. Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment. DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.
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影响因子：
8.8
作者：
Michelakis, E. D.;Webster, L.;Mackey, J. R.
通讯作者：
Mackey, J. R.
影响因子：
3.8
作者：
Sun, Ramon C.;Fadia, Mitali;Blackburn, Anneke C.
通讯作者：
Blackburn, Anneke C.
影响因子：
10.4
作者：
Carter, Julia H;Carter, Harry W;Deddens, James A;Hurst, Bernadette M;George, Michael H;DeAngelo, Anthony B
通讯作者：
DeAngelo, Anthony B
影响因子：
11.2
作者：
Rofstad, Einar K.;Mathiesen, Berit;Galappathi, Kanthi
通讯作者：
Galappathi, Kanthi
DOI：
10.1152/ajpcell.2001.281.2.c430
发表时间：
2001-08-01
影响因子：
5.5
作者：
Cheng, AM;Morrison, SW;Hagen, SJ
通讯作者：
Hagen, SJ