An anticancer agent, pyrvinium pamoate inhibits the NADH–fumarate reductase system—a unique mitochondrial energy metabolism in tumour microenvironments

Abstract

Increased glycolysis is the principal explanation for how cancer cells generate energy in the absence of oxygen. However, in actual human tumour microenvironments, hypoxia is often associated with hypoglycemia because of the poor blood supply. Therefore, glycolysis cannot be the sole mechanism for the maintenance of the energy status in cancers. To understand energy metabolism in cancer cells under hypoxia-hypoglycemic conditions mimicking the tumour microenvironments, we examined the NADH-fumarate reductase (NADH-FR) system, which functions in parasites under hypoxic condition, as a candidate mechanism. In human cancer cells (DLD-1, Panc-1 and HepG2) cultured under hypoxic-hypoglycemic conditions, NADH-FR activity, which is composed of the activities of complex I (NADH-ubiquinone reductase) and the reverse reaction of complex II (quinol-FR), increased, whereas NADH-oxidase activity decreased. Pyrvinium pamoate (PP), which is an anthelmintic and has an anti-cancer effect within tumour-mimicking microenvironments, inhibited NADH-FR activities in both parasites and mammalian mitochondria. Moreover, PP increased the activity of complex II (succinate-ubiquinone reductase) in mitochondria from human cancer cells cultured under normoxia-normoglycemic conditions but not under hypoxia-hypoglycemic conditions. These results indicate that the NADH-FR system may be important for maintaining mitochondrial energy production in tumour microenvironments and suggest its potential use as a novel therapeutic target.

Cancer Usurps Skeletal Muscle as an Energy Repository

“…Some "aberrant" energy production systems have been reported in cancer cells. For adapting hypoxic-hypoglucemic condition, some cancer uses fumarate as an energy source, which is known to occur in parasites (41).…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Anticancer activities of several anthelminthics attracted considerable interest, especially their capacity to target signal transduction pathways of CSCs/TICs of several tumor types. Aside of the inhibition of signal transduction, on-target repositioning assumes that the targets recognized in nematods, such as mitochondrial respiration and microtubules, are hit in cancer cells [70,89,90]. However, the multitude of effects observed in response to the anthelminthics cannot be explained by specific and defined intracellular targets.…”

“…In particular, glucose utilization and related unfolded protein response as well as autophagy were reported to become deranged in diverse cancer cells [8,72,73]. Pyrvinium-induced cell death was associated with defective mitochondrial respiration in diverse cancers, breast CSC-like cells and lymphoma, the latter involving regulation of JAK2/STAT5 signaling [60,[68][69][70]. Several studies reported the Wnt pathway as target of pyrvinium, especially in breast and lung CSCs [56,63,64].…”

Assessment of Anticancer Drug Effects on Pancreatic Cancer Cells under Glucose-Depleted Conditions Using Intracellular and Extracellular Amino Acid Metabolomics

“…These results showed that PP is more effective under hypoglycemic conditions, which is consistent with the results of previous studies. [21][22][23][24] To evaluate the amino acid metabolic alterations upon these treatments, PANC-1 cells, cultured as described above, were analyzed by amino acid metabolomics.…”

“…PP selectively inhibits the reduced nicotinamide adenine dinucleotide (NADH)-fumarate reductase in the respiratory chain. [22][23][24] Amino acids are thought to be used instead of glucose in the NADH-fumarate reductase system because aspartic acid is converted into fumarate. The results obtained provide useful information that will improve our understanding of the metabolic characteristics of cancer cells.…”