Effects of three modifiers of glycolysis on ATP, lactate, hypoxia, and growth in human tumor cell lines in vivo.

BACKGROUND: High pretreatment tumor lactate content is associated with poor outcome after fractionated irradiation in human squamous cell carcinoma (hSCC) xenografts. Therefore, decreasing lactate content might be a promising approach for increasing tumor radiosensitivity. As the basis for such experiments, the effects of the biochemical inhibitors pyruvate dehydrogenase kinase dichloroacetate (DCA), lactate dehydrogenase oxamate, and monocarboxylic acid transporter-1 α-cyano-4-hydroxycinnamate (CHC) on tumor micromilieu and growth were investigated. MATERIALS AND METHODS: Oxygen consumption (OCR) and extracellular acidification rates (ECAR) were measured in FaDu and UT-SCC-5 hSCC in response to DCA in vitro. Mice bearing FaDu, UT-SCC-5, and WiDr colorectal adenocarcinoma received either DCA in drinking water or DCA injected twice a day, or CHC injected daily. WiDr was also treated daily with oxamate. FaDu and UT-SCC-5 were either excised 8 days after treatment for histology or tumor growth was monitored. WiDr tumors were excised at 8 mm. Effect of inhibitors on ATP, lactate, hypoxia, and Ki67 labeling index (LI) was evaluated. RESULTS: DCA increased OCR and decreased ECAR in vitro. None of the treatments with inhibitors significantly changed lactate content, hypoxia levels, and Ki67 LI in the three tumor lines in vivo. ATP concentration significantly decreased after only daily twice injections of DCA in FaDu accompanied by a significant increase in necrotic fraction. Tumor growth was not affected by any of the treatments. CONCLUSION: Overall, tumor micromilieu and tumor growth could not be changed by glycolysis modifiers in the three tumor cell lines in vivo. Further studies are necessary to explore the impact of metabolic targets on radiation response.

Manipulation of glycolysis in malignant tumors: fantasy or therapy?

After Warburg stated his hypothesis on tumor cell metabolism about 80 years ago, the field of carbohydrate metabolism of cancer cells and solid tumors is experiencing a boom for the past few years. Numerous studies have been focused on the characteristics of cancer metabolism and its accessibility to novel therapeutic interventions. Malignant transformation is associated with an increase in glycolytic flux, mainly caused by an upregulation of numerous glycolysis-related genes in the majority of human cancers. As a consequence of these alterations, tumor cells are producing lactate at higher levels compared to non-malignant tissue, even in the presence of oxygen, a phenomenon termed "aerobic glycolysis" or "Warburg effect". A correlation between alterations in glycolytic pathways and therapy resistance in tumors is partially due to radical scavenger properties of specific metabolites which may decrease therapy-induced radical formation. Glycolytic activity and glycolysis-linked metabolic milieu are often variable between individual tumors resulting in variations in treatment response and aggressiveness. The peculiarities of tumor cell metabolism can be utilized for cancer diagnostics, such as metabolic imaging techniques and metabolic tumor markers. An emerging field of research is the manipulation of tumor cell metabolism for therapeutic purposes; respective studies include approaches of glycolysis inhibition or forcing mitochondrial respiration, respectively, based on biochemical and molecular principles. Up to now, such approach could eliminate tumors in patients without side effects when applied as single drug. Nevertheless, several agents that manipulate tumor metabolism may become a supportive therapy in combination with established cancer treatments.

[Lactate and redox status in malignant tumors]. / Laktat und Redoxstatus in malignen Tumoren.

This article summarizes data from experimental and clinical oncology which are indicative of a pivotal role of tumor carbohydrate metabolism in malignant behavior and outcome of treatment. In primary tumors, such as cervix carcinomas, head and neck squamous cell carcinomas or rectum adenocarcinomas, elevated lactate levels as a mirror of a high glycolytic activity, are correlated even at the initial diagnosis with a high level of malignancy as indicated by increased formation of metastases or an elevated radiotherapy resistance. The relationship between therapeutic resistance and glycolysis may at least partially be due to the radical scavenging potential of glycolytic intermediates, mainly pyruvate and lactate and to the link between these metabolites and the cellular redox status. On the basis of these data and other considerations, a novel technique has been developed for imaging the lactate/pyruvate ratio in tumor biopsies using quantitative bioluminescence. More research effort should, therefore, be focussed on the redox status of tumors in oncological studies in the future.