Background Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (-F1-ATPase). bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. Conclusions Overall, we suggest that the determination of the bioenergetic signature of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression. Background Colorectal cancer (CRC) is a common neoplasia which poses a heavy burden on public health systems worldwide . Despite the establishment of CRC screening protocols, tailored therapeutic approaches are required to minimize the significant social impact of this disease . At present, KRAS mutation status is the only validated predictive marker for targeted CRC therapy . Thus, the development and clinical implementation of new predictive molecular markers are needed to aid in the selection of patients likely to respond to therapy and rationalized CRC treatments . Cancer cells and tumors have a predominant glycolytic metabolism, even under aerobic conditions [3,4]. Although the altered energetic Siramesine metabolism of cancer cells has been proposed as a potential target for cancer treatment [3,5-7], it could also represent a therapeutic obstacle, because of its contribution to chemo- and radio-resistance . In some tumors, this glycolytic phenotype is accompanied by a Siramesine loss of bioenergetic activity in mitochondria [9,10], which can be estimated by determining its bioenergetic signature [10,11]. The bioenergetic signature is a protein ratio (-F1-ATPase/GAPDH ratio) that assesses the expression of the catalytic subunit of mitochondrial H+-ATP synthase (-F1-ATPase), a bottle-neck component required for the synthesis of biological energy, relative to the expression of glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) . Consistently, the bioenergetic signature has been observed to be significantly down-regulated in different human tumors compared to paired normal tissues [10,12-19]. Recent findings indicate that the bioenergetic signature also represents a functional index of metabolic activity because it correlates, both in vivo and in vitro, with the rate of glucose utilization by cancer cells and tumors [9,11]. Moreover, according to large cohort studies of colon [10,19], lung [9,14] and breast [16,20] cancer patients, low tumor bioenergetic signatures are associated with poor patient prognosis, strongly suggesting that impaired mitochondrial bioenergetics is at the Siramesine heart of cancer progression. Remarkably, down-regulation of -F1-ATPase has been widely associated with the resistance of cancer cells to standard anticancer therapies [21-23]. In the specific case of colon cancer cells, Amotl1 chemotherapeutic response to 5-fluorouracil (5-FU) [11,21], as well Siramesine as several metabolic inhibitors [23,24], was assessed in cells with different genetic backgrounds: a condition that is likely to affect the cellular response to chemotherapeutic agents. The recent development of isogenic HCT116 colon cancer cell lines, representing different bioenergetic signatures , has provided an opportunity to unambiguously assess the influence of energetic metabolism on colon cancer therapy. In this study, we investigated cell death responses in metabolically different isogenic HCT116 cells and the regression of tumor xenographs, in response to the glycolytic inhibitors 3-bromopyruvate (3BrP) and iodoacetate (IA), and the classic Siramesine chemotherapeutic agent, 5-FU. The small alkylating 3BrP and IA target the enzymes of glycolysis hexokinase  and GAPDH , respectively, although recent findings.