title: 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.
authors.affiliation: Cancer Physiology Project, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. e-tomi@humeco.m.u-tokyo.ac.jp
authors.forename: Eriko
authors.initials: E
authors.lastname: Tomitsuka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017165:Ascaris suum / Q000187:drug effects; D002417:Cattle; D015687:Cell Hypoxia; D042963:Electron Transport Complex II / Q000378:metabolism; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011774:Pyrvinium Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000871:Anthelmintics; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011774:Pyrvinium Compounds; C024631:pyrvinium; D044925:Oxidoreductases Acting on CH-CH Group Donors; C020155:fumarate reductase (NADH); D042963:Electron Transport Complex II