Aerobic glycolysis is common particularly in aggressive tumors, though the causative relationship remains unknown. The specificity of SDH loss in PGL has led to the hypothesis that it is succinate accumulation, not just TCA cycle dysfunction, that is pathogenic. As described above, the detection of approved LOPAC drugs disulfiram and dequalinium among compounds differentially toxic to sdh2D mutant yeast cells is interesting and provocative. These agents have been proposed as anti-malarials, with disulfiram as a potential inhibitor of AZD6244 606143-52-6 alcohol dehydrogenase and dequalinium potentially increasing reactive oxygen species, a stress already known to be higher in sdh2D mutant yeast. Interestingly, six of the ten compounds identified by the main HTS are potentially chemically reactive as Michael acceptors. Related compounds are sometimes categorized as pan assay interference “PAINS” compounds that can be problematic in HTS by interference with fluorescent detection or other technical problems. However, it must be noted that these compounds were identified here in a simple differential growth screening protocol that avoids nonspecific effects commonly associated with PAINS compounds. In fact, the compounds shown in Fig. 6 reflect potentially reactive agents as have been enjoying a resurgence in medicinal chemistry through covalent mechanisms including thiol-reactivity. With respect to possible mechanisms of differential toxicity to sdh2D mutant yeast cells, the most obvious a priori targets include the unique reliance of sdh2D mutant cells on glycolysis and the potentially stressful increases in intracellular ROS and Su. If each of these characteristics holds for SDH mutant human PGL tumor cells, rational approaches might be imagined. In the simplest case, PGL cells could be starved by providing only nonfermentable carbon sources if metabolism in other tissues could be supported by ketogenic agents. Our HTS screening results add insights into possible clinical tactics against SDH mutant cells such s SDH-mutant PGL. Our observation that alcohol dehydrogenase inhibitors are differentially toxic to sdh2D mutant yeast is interesting and provocative. Disulfiram is an approved anti-alcoholism medication shown to inhibit both FTY720 aldehyde dehydrogenase and alcohol dehydrogenase. Disulfiram is also an anti-malarial, noteworthy because, like PGL cells, P. falciparum cells lack a TCA cycle and rely on glycolysis. Moreover, we have now shown that four of the ten leading differential inhibitors of sdh2D mutant yeast growth are inhibitors of yeast alcohol dehydrogenase. This result points to glycolysis inhibition as an interesting approach in human PGL. In the absence of a TCA cycle, NAD + recycling to NADH might become limiting for PGL tumor cells. Yeast uses pyruvate decarboxylase to convert pyruvate to acetaldehyde and then alcohol dehydrogenase to regenerate NAD + by reduction of acetaldehyde to ethanol at the expense of NADH. Mammals accomplish the same NAD + regeneration by reducing pyruvate to lactate using lactate dehydrogenase. Thus, by analogy with the results of this high-throughput screen, an interesting target for therapeutic inhibition of SDH mutant PGL would be lactate dehydrogenase. We confirm this concept here by showing that human cells deficient in SDH activity are differentially sensitive to the lactate dehydrogenase inhibitor oxamate. This provocative result points to the potential value of lactate dehydrogenase inhibitors in paraganglioma therapy.