Separate and concurrent use of 2-deoxy-D-glucose and 3-bromopyruvate             in pancreatic cancer cells.
Unrestrained glycolysis characterizes energy meta-bolism in cancer cells.             Thus, antiglycolytic reagents such as 2-deoxy-D-glucose (2-DG) and 3-bromopyruvate             (3-BrPA) may be used as anticancer drugs. In the present study, we examined the             anticancer effects of 2-DG and 3-BrPA in pancreatic cancer cells and investigated             whether these effects were regulated by hypoxia-inducible factor-1α (HIF-1α).             To this end, 2-DG and 3-BrPA were administered to wild-type (wt) MiaPaCa2 and             Panc-1 pancreatic cancer cells that were incubated under hypoxic (HIF-1α-positive)             or normoxic (HIF-1α-negative) conditions. In addition, 2-DG and 3-BrPA were also             administered to si-MiaPaCa2 and si-Panc-1 cells that lacked HIF-1α as a result             of RNA interference. Following drug exposure, cell population was measured using             a viability assay. Both HIF-1α-positive and HIF-1α-negative MiaPaCa2 cells were             further studied for their expression of Cu/Zn-superoxide dismutase (SOD1) and             poly(ADP-ribose) polymerase (PARP) and for their contents of ATP and fumarate.             In the viability assay, either 2-DG or 3-BrPA decreased the tested cells. Concurrent             use of 2-DG and 3-BrPA resulted in a greater decrease of cells and also facilitated             ATP depletion. In addition, 3-BrPA was seen to both decrease SOD1 and increase             fumarate, which suggests that the reagent impaired the mitochondria. 3-BrPA also             decreased both full-length PARP and cleaved PARP, which suggests that 3-BrPA-induced             decrease in cell population was a result of cell necrosis rather than apoptosis.             When HIF-1α was induced in wt-MiaPaCa2 cells by hypoxia, some effects of 2-DG             and 3-BrPA were attenuated. We conclude that: i) concurrent use of 2-DG and 3-BrPA             has better anticancer effects in pancreatic cancer cells, ii) 3-BrPA impairs the             mitochondria of pancreatic cancer cells and induces cell necrosis, and iii) HIF-1α             regulates the anticancer effects of 2-DG and 3-BrPA in pancreatic cancer cells.
Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China.
Huijie
H
Xiao
Shasha
S
Li
Dapeng
D
Zhang
Tongjun
T
Liu
Ming
M
Yu
Feng
F
Wang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005650:Fumarates / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D011773:Pyruvates / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D004791:Enzyme Inhibitors; D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D034741:RNA, Small Interfering; C017092:bromopyruvate; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases