Ho C-L, Yu SCH, Yeung DWC. positron emission tomography ((18F)-FDG-PET). 2-DG has broad anti-proliferative effects on cancer cells and and was evaluated in a number of clinical trials ([31], reviewed in [50]). To be effective, 2-DG must out-compete glucose which is present at millimolar concentrations in the blood; at tolerated doses, 2-DG had no measurable anti-tumor activity [4]. Thus, while GLUTs play a key role in supporting malignant growth and pre-clinical studies strongly suggest that GLUT1 and GLUT3 will be excellent targets for anti-anabolic cancer therapies, new small molecules or gene delivery approaches will be required before NOS3 GLUTs can be targeted successfully in the clinic. Structures are available for several GLUT family members, including GLUT1 and GLUT3, which could facilitate drug development ([51C53], reviewed in [54,55]). As GLUT1 deficiency leads to a spectrum of neurological symptoms, toxicity may impede the development of GLUT1 inhibitors for cancer patients. However, cancers with gross overexpression of GLUTs and mutations that addict them to glucose metabolism may be exquisitely sensitive to inhibition producing an acceptable therapeutic index. In addition to the facilitative GLUT family of glucose transporters, the sodium-coupled glucose transporters (SLC5A family, SGLTs) that are normally expressed in the intestine and kidney are also up-regulated in some cancers. Because the Na+ gradient generated by the Na+/K+ ATPase is used to transport glucose, SGLTs can transport glucose against its concentration gradient at the cost of ATP hydrolysis. SGLT1 and SGLT2 expression is elevated prostate and pancreatic tumors where it increases uptake of Me4FDG (Me4FDG is usually a SGLT but not GLUT substrate, while 2-FDG commonly used for (18F)-FDG-PET is usually a GLUT but not a SGLT substrate) [56]. An SGLT2 inhibitor FDA-approved for type 2 diabetes, dapagliflozin, inhibited Me4FDG uptake by prostate and pancreatic xenografts [58]. It is possible that this SGLTs play a critical role in poorly perfused areas of solid tumors where glucose levels are low and GLUTs ineffective because active transport is required to import glucose. Monocarboxylate transporters that import lactate and acetate The monocarboxylate transporters MCT1 (SLC16A1) and MCT4 (SLC16A3) also contribute to oncogenic anabolism. MCT1 and MCT4 perform proton-coupled transport of pyruvate, lactate, and acetate. MCT1 has a wide tissue distribution, whereas MCT4 expression prevents lactic acid build-up in highly glycolytic cells [59,60] (reviewed in [61]). While MCT4 supports malignancy anabolism by exporting lactate to maintain lactate dehydrogenase activity and NAD+ production for glycolysis, MCTs also import anabolic substrates. Although often considered only as a toxic by-product of glycolysis, lactate is an energy-rich molecule that is used as fuel by MCT1-expressing cancer cells [62C64]. Indeed, lactate shuttling coordinated by the expression of different MCTs has been described between tumor cells with glycolytic (export) and oxidative (import) profiles. For example, oxygenated tumor cells that express MCT1 can spare glucose for use by hypoxic cells by oxidizing lactate, creating a symbiotic relationship between tumor cells in perfused and hypoxic areas [64]. Notably, this metabolic symbiosis is also observed between tumor and cancer-associated fibroblasts (CAFs) reprogrammed toward aerobic glycolysis by factors secreted by tumors, a phenomenon coined the reverse Warburg effect [65]. Feedback signals from the stroma lead to a reciprocal metabolic shift in the tumor, notably an up-regulation of MCT1, allowing lactate exported by CAFs to be used to support tumor growth in tumor cells [66]. Breaking this lactate cycle via inhibition of MCT1, MCT4, or both may Bronopol be another way to starve cancer cells for fuel provided that normal cells that rely on MCTs (e.g. red blood cells) can tolerate their inhibition. While under standard growth conditions Bronopol 90% of acetyl CoA is derived from glucose or glutamine, a series of recent studies show that hypoxia and low nutrient conditions increase utilization of exogenous acetate for lipid synthesis and tumor growth [67C70]. Acetate is usually Bronopol imported via MCTs, and thus tumors using acetate as a metabolic fuel would also be sensitive to MCT inhibitors. Oxidation of acetate occurs in both orthotopic glioma xenografts and brain metastases of other tumor types with a variety of oncogenic mutations [70]. Given that the primary tumors from which the metastases were derived are not generally 11C-acetate-PET positive, the brain microenvironment may favor the use of acetate as a metabolic fuel. Acetate oxidation was confirmed in glioma patients using isotopic tracing demonstrating that acetate is an important anabolic fuel under physiologic conditions, consistent with 11C-acetate-PET labeling of brain tumors [70,71]. Liver, renal, and prostate tumors as well as some multiple myelomas have been found to be 11C-acetate consumers [72C77]. In summary, acetate is usually a previously under-appreciated anabolic fuel for cancer cells, particularly under suboptimal growth conditions, and inhibiting acetate import could be a valuable starvation strategy. MCTs require the chaperone CD147 (basigin) for cell surface.