Wakiyama, KotaKitajima, YoshihikoTanaka, TomokazuKaneki, MasaoYanagihara, KazuyoshiAishima, ShinichiNakamura, JunNoshiro, Hirokazu2017-12-062017Wakiyama, Kota, Yoshihiko Kitajima, Tomokazu Tanaka, Masao Kaneki, Kazuyoshi Yanagihara, Shinichi Aishima, Jun Nakamura, and Hirokazu Noshiro. 2017. “Low-dose YC-1 combined with glucose and insulin selectively induces apoptosis in hypoxic gastric carcinoma cells by inhibiting anaerobic glycolysis.” Scientific Reports 7 (1): 12653. doi:10.1038/s41598-017-12929-9. http://dx.doi.org/10.1038/s41598-017-12929-9.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492360This study aimed to establish a therapeutic strategy targeting hypoxic cancer cells in gastric carcinoma (GC). YC-1 is a HIF-1α inhibitor, and we revealed that low-dose YC-1 (10 µM) suppressed HIF-1α expression, and induced hypoxia-dependent apoptosis in the GC cell line 58As9. This hypoxia-specific apoptosis induction by YC-1 involved excessive reactive oxygen species (ROS) generation. The apoptotic effect of 10 µM YC-1 was enhanced by additional glucose (G) and insulin (I) treatments. RT-PCR demonstrated that 10 µM YC-1 reduced hypoxia-induced expression of HIF-1α targets involved in anaerobic glycolysis. Metabolic analysis showed that YC-1 shifted glucose metabolism in hypoxic cells from anaerobic glycolysis to oxidative phosphorylation (OXPHOS). Additional GI accelerated membranous GLUT1 translocation, elevating glucose uptake, and increased acetyl-CoA levels, leading to more ROS generation in hypoxic YC-1-treated cells. Finally, we evaluated the anti-cancer effect of low-dose YC-1 (1 mg/kg) + G (2 g/kg) and I (1 unit/3 g G) treatment in xenograft models. YC-1 + GI therapy strongly inhibited tumour growth. Immunohistochemical analysis demonstrated that YC-1 + GI reduced HIF-1α expression and pimonidazole accumulation in tumours. Conversely, YC-1 + GI increased intra-tumoral 8-OHdG and levels of apoptosis markers. Low-dose YC-1 + GI is a unique therapy targeting hypoxic GC cells that generates lethal ROS via forced activation of OXPHOS.en-USJournal Article2017-12-0610.1038/s41598-017-12929-9