Glucose Deprivation‐Induced Oxidative Stress in Human Tumor Cells: A Fundamental Defect in Metabolism?

Abstract

A BSTRACT : Recently, glucose deprivation-induced oxidative stress has been shown to cause cytotoxicity, activation of signal transduction (i.e., ERK1, ERK2, JNK, and Lyn kinase), and increased expression of genes associated with malignancy (i.e., bFGF and c-Myc) in MCF-7/ADR human breast cancer cells. These results have led to the proposal that intracellular oxidation/ reduction reactions involving hydroperoxides and thiols may provide a mechanistic link between metabolism, signal transduction, and gene expression in these human tumor cells. The current study shows that several other transformed human cell types appear to be more susceptible to glucose deprivationinduced cytotoxicity and oxidative stress than untransformed human cell types. In a matched pair of normal and SV40-transformed human fibroblasts the cytotoxic process is shown to be dependent upon ambient O 2 concentration. A theoretical model to explain the results is presented and implications to unifying modern theories of cancer are discussed.

2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress

“…The biochemical rationale for this combination to enhance cancer cell killing was based on previous results in other human cancer cells suggesting that 2DG would inhibit glucose metabolism leading to a reduction in intracellular pyruvate and NADPH [3,4,37], limiting the capacity of the tumor cells to metabolize hydroperoxides [4,15,25], and p53 would increase metabolic hydroperoxide production [1,2,20,36] leading to enhanced oxidative stress. As shown in our results the combination of 2DG and Adp53 lead to over expression of p53 (Figure 1), increased clonogenic cell killing (Figure 2 and Figure 3), and increased oxidative stress that appeared to be mediated by increased steady-state levels of hydroperoxides including H 2 O 2 (Fig 4-Fig 6) in prostate cancer cells.…”

“…Samples were thawed and whole homogenates were prepared as described [3,4,15,22,23]. Total glutathione (GSH+GSSG), and glutathione disulfide (GSSG) were determined using a spectrophotometric recycling assay [3,4,15,22,23].…”

“…Since glucose is a major source of electrons for hydroperoxide metabolism [15][16][17][18] and tumor cells are believed to produce relatively high steady-state levels of hydroperoxides [19], the mechanism by which 2DG enhances oxidative stress in cancer cells was suggested to involve limitation of hydroperoxide detoxification [4]. Recently p53-induced apoptosis in cancer cells has been shown to occur through induction of p53-induced genes (PIGs) and the tumor suppressive effects of some PIGs are thought to be the result of increased formation of reactive oxygen species and mitochondrial respiration (ROS) (i.e.…”

“…O 2 •-and H 2 O 2 ), which in turn lead to oxidative stress [1,2,9,10,20]. Since 2DG would be expected to inhibit the formation of pyruvate and NADPH, which function in the detoxification pathways of H 2 O 2 [3,4,15], we hypothesized that the combination of 2DG and wt p53 over expression would lead to increased steady-state levels of ROS and enhanced cell killing by oxidative stress. In the current report, the interaction between 2DG and p53 gene therapy in two androgen-independent prostate cancer cell lines (DU-145 and PC-3) was evaluated in vitro.…”

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

“…To reduce transgene expression in normal tissues, unique promoters have been integrated into viral vectors. These promoters can be activated only by specific stimuli in tumours that are either endogenous or applied externally (Vaupel et al, 1989;Gossen and Bujard, 1992;Garver et al, 1994;Harris et al, 1994;Hallahan et al, 1995;Kumagai et al, 1996;Jaggar et al, 1997;Jenster et al, 1997;Blackburn et al, 1998;Chung et al, 1999;Abdul-Ghani et al, 2000;Huang et al, 2000;Koshikawa et al, 2000;Pollock et al, 2000;Spitz et al, 2000). However, the control of transgene expression will not reduce the acute toxicity in normal tissues caused by viral proteins.…”