Abstract During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy. 

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Targeting mitochondrial metabolism for precision medicine in cancer

Targeting lactate metabolism for cancer immunotherapy - a matter of precision.

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect

Sulfonamides, with the general formula R-SO2NR1R2, have attracted great attention since the early discovery of sulfonamide-containing antibacterial drugs. The combinations of certain sulfonamides and other drug molecules to form sulfonamide hybrids are being used to develop novel formulations with greater effectiveness and in a huge range of therapeutic applications such as antimicrobial, antifungal, anti-inflammatory, antitubercular, antiviral, antidiabetic, antiproliferative, carbonic anhydrase inhibitor, antimalarial, anticancer and other medicinal agents. Part C of this review presents recent advances in designing and developing multicomponent sulfonamide hybrids containing more than one biologically active heterocycle, such as coumarin, indole, pyridine, pyrimidine, pyrazole, triazole, oxazole, oxadiazole, triazine, quinazoline, and thiadiazol. This review aims to highlight the status of the hybridization technique in synthesizing biological and computational studies of novel sulfonamide hybrids that were designed and presented between 2016 and 2020.

Recent Advances in Biological Active Sulfonamide-based Hybrid Compounds Part C: Multicomponent Sulfonamide Hybrids.

Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of NADH as the final step in the glycolytic pathway. Glycolysis plays an important role in th...

Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.

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Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.