Enhanced radiosensitivity and chemosensitivity of breast cancer cells by 2-deoxy-d-glucose in combination therapy

Abstract

Breast cancer is the most common malignancy, and it is also the major cause of cancer-related deaths of women worldwide. Breast cancer treatment involves surgery, chemotherapy, radiation therapy, or combination therapy, and novel strategies are needed to boost the oncologic outcome. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) which inhibits glucose synthesis and adenosine triphosphate production, is one of the important discoveries involving the disturbances that can be caused to the process of the metabolism. The glucose analogue, 2-DG, is known as a tumor sensitizer to irradiation (IR) and chemotherapy, which help improve the treatment rates. It enhances the cytotoxicity via oxidative stress, which is more redundant in tumor cells than in normal ones. This article provides a brief summary on studies related to 2-DG chemo-/radio-sensitization effects by combination therapy of 2-DG/IR or 2-DG/doxorubicin.

Keywords: 2-deoxy-D-glucose; Breast neoplasms; Combined modality therapy; Radiation; Tumor cell line.

Figure 1

Glycolytic pathway and its metabolic interconnection with the pentose-phosphate pathway. The solid arrows indicate glycolytic reactions, whereas the dashed arrows show the pentose-phosphate pathway. The green arrows indicate further metabolism of pyruvate downstream of glycolysis. Pentavalent arsenic compound (H₃AsO₄) abolishes adenosine triphosphate (ATP) generation by causing arsenolysis in the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reaction (From Pelicano H, et al. Oncogene 2006;25:4633-46, with permission) [16]. HK=hexokinase; PGI=phosphoglucose isomerase; PFK=phosphofructokinase; TPI=triosephosphate isomerase; PGK=phosphoglycerate kinase; PGM=phosphoglycerate mutase; PK=pyruvate kinase; PDH=pyruvate dehydrogenase; LDH=lactate dehydrogenase.

Figure 2

(A) Structural comparison of glucose and 2-deoxy-D-glucose (2-DG). 2-DG and glucose differ at the second carbon. (B) Schematic diagram of 2-DG action. 2-DG enters the cell through the glucose transporter and is phosphorylated by hexokinase. Because of low levels of intracellular phosphatase, 2-DG-PO4 is trapped in the cell. 2-DG-PO4 is unable to undergo further metabolism. High intracellular levels of 2-DG-6-PO4 cause allosteric and competitive inhibition of hexokinase. This results in inhibition of glucose metabolism (From Aft RL, et al. [17] Br J Cancer 2002;87:805-12, with permission from publisher).

Figure 3

Summary of drug combinations with 2-deoxy-D-glucose SKBR3 cells incubated with the indicated agent for 24 hours (From Zhang F, et al. [21] J Cancer Res Ther 2009;5 Suppl 1:S41-3, permitted to use without a prior permission from the publisher).