The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines

Purpose: the anti-tumor activity of glucose analogs 2-deoxy-glucose (2-dg) and d-allose was investigated alone or in combination with p38 mitogen-activated protein kinase (mapk) inhibitor sb202190 or platinum analogs as a strategy to pharmacologically target glycolytic tumor phenotypes. methods: hypoxia inducible factor-1 alpha (hif-1α) protein accumulation in pancreatic cell lines treated with sb202190 alone and in combination with glucose analogs was analyzed by western blot. hif-1α transcriptional activity was measured in mia paca-2 cells stably transfected with a hypoxia response element luciferase reporter following treatment with glucose analogs alone,and in combination with sb202190. induction of cleaved poly(adp-ribose) polymerase (parp) was measured by western blot in the mia paca-2 cells. in vitro anti-proliferative activity of 2-dg and d-allose alone,or in combination with oxaliplatin (pancreatic cell lines),cisplatin (ovarian cell lines),or with sb202190 were investigated using the mtt assay. results: sb202190 decreased hif-1α protein accumulation and transcriptional activity. 2-dg demonstrated greater anti-proliferative activity than d-allose. pre-treatment with sb202190 enhanced activity of both 2-dg and d-allose in mia paca-2,bxpc-3,aspc-1,and sk-ov-3 cells. the combination of d-allose and platinum agents was additive to moderately synergistic in all but the ovcar-3 and hey cells. sb202190 pre-treatment further enhanced activity of d-allose and 2-dg with platinum agents in most cell lines investigated. conclusions: sb202190 induced sensitization of tumor cells to 2-dg and d-allose may be partially mediated by inhibition of hif-1α activity. combining glucose analogs and p38 mapk inhibitors with chemotherapy may be an effective approach to target glycolytic tumor phenotypes. © 2015 malm et al.; licensee biomed central.