Mitochondrial fumarate reductase as a target of chemotherapy: from parasites to cancer cells.
Recent research on respiratory chain of the parasitic helminth, Ascaris suum has shown that the mitochondrial NADH-fumarate reductase system (fumarate respiration), which is composed of complex I (NADH-rhodoquinone reductase), rhodoquinone and complex II (rhodoquinol-fumarate reductase) plays an important role in the anaerobic energy metabolism of adult parasites inhabiting hosts. The enzymes in these parasite-specific pathways are potential target for chemotherapy. We isolated a novel compound, nafuredin, from Aspergillus niger, which inhibits NADH-fumarate reductase in helminth mitochondria at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep indicating that mitochondrial complex I is a promising target for chemotherapy. In addition to complex I, complex II is a good target because its catalytic direction is reverse of succinate-ubiquionone reductase in the host complex II. Furthermore, we found atpenin and flutolanil strongly and specifically inhibit mitochondrial complex II. Interestingly, fumarate respiration was found not only in the parasites but also in some types of human cancer cells. Analysis of the mitochondria from the cancer cells identified an anthelminthic as a specific inhibitor of the fumarate respiration. Role of isoforms of human complex II in the hypoxic condition of cancer cells and fetal tissues is a challenge. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.
Department of Biomedical Chemistry, The University of Tokyo, Tokyo, Japan.
Chika
C
Sakai
Eriko
E
Tomitsuka
Hiroyasu
H
Esumi
Shigeharu
S
Harada
Kiyoshi
K
Kita
D000328:Adult; D000818:Animals; D000977:Antiparasitic Agents / Q000627:therapeutic use*; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010271:Parasites / Q000187:drug effects*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000977:Antiparasitic Agents; D009097:Multienzyme Complexes; D013385:Succinate Dehydrogenase