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.