Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells

Abstract

Increasing evidence suggests that cancer cells (relative to normal cells) have altered mitochondrial electron transport chains (ETC) that

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

“…Mimicking glucose deprivation, 2DG potently induces mitochondrial oxidative stress [36]. The phosphorylated product of 2DG, 2DG-6-P, can only undergo the first enzymatic reaction in the PPP by glucose-6-phosphate dehydrogenase (G-6-PD) to regenerate one molecule of NADPH from NADP+, but the product 2-Deoxy-D-glucose-6-phosphoglaconalactone cannot be further metabolized to generate the second molecule of NADPH [49,54]. In general, treatment with 2DG results in pyruvate and NADPH deficiencies, damaging the antioxidant defenses of cancer cells and may render them more vulnerable to oxidative stress induced by radiotherapy or chemotherapy.…”

Glycolysis inhibition by 2-deoxy-d-glucose reverts the metastatic phenotype in vitro and in vivo

“…A natural possibility would be to concurrently inhibit the mitochondria themselves through the use of electron transport chain decouplers such as antimycin A or rotenone. It has previously been shown that the combination of 2DG and these compounds makes cells more sensitive to 2DG by increasing ROS, as glucose may act as an inhibitor of ROS production, and decreasing available NADPH in the pentose phosphate shunt [41,42]. Increased ROS may be exploited through radiation therapy in conjunction with 2DG as previously described [32].…”

Manipulation of tumor metabolism for therapeutic approaches: ovarian cancer-derived cell lines as a model system

“…These specific manipulations may serve as a model for radio-sensitizing tumor cells [24,27]. A possible therapeutic approach of targeting metabolic pathways with 2DG is currently used in several clinical trials (phase I/II) in different solid tumors [28].…”

“…Oxidative stress caused by increased ROS generation seems to be a common feature of cancer cells, at least in part due to respiratory chain malfunction [22,23]. This makes cancer cells more vulnerable to damage by additional ROS, either through inhibiting ROS scavenger systems or through enhancing ROS generation [24][25][26]. As both cell lines maintained their metabolic and proteomic phenotype, even as Fig.…”