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

Journal of Experimental & Clinical Cancer Research

Amanda F Baker²  Liliana Carbajal²  Alexander Gill²  Neale T Hanke²  Scott W Malm¹ 

[1] College of Pharmacy, University of Arizona, Tucson, Arizona, USA;College of Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA

关键词: p38 mitogen activated protein kinase;    Ovarian cancer;    Pancreatic cancer;    Hypoxia inducible factor 1α;    D-allose;    2-deoxy-glucose;   

Others  :  1161141
DOI  :  10.1186/s13046-015-0147-4

 received in 2015-02-03, accepted in 2015-03-16,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Malm et al.; licensee BioMed Central.

【 图 表 】

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