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REVIEW ARTICLE
Year : 2009  |  Volume : 5  |  Issue : 9  |  Page : 27-31

Cytotoxicity,radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose In vitro


Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India

Date of Web Publication21-Aug-2009

Correspondence Address:
B S Dwarakanath
Institute of Nuclear Medicine and Allied Sciences, New Delhi - 110 054
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.55137

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 > Abstract 

The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibition of cell proliferation and induction of apoptosis have been observed as cytotoxic effects in a wide variety of tumor cells in vitro, while sensitization of tumor cells to ionizing radiation and certain chemotherapeutic drugs is associated with enhanced mitotic as well as apoptotic cell death induced by the primary therapeutic agent. Therefore, there has been a considerable amount of interest in developing 2-DG as a therapeutic agent or adjuvant in the radiotherapy and chemotherapy of tumors.

Keywords: Radiosensitization, chemosensitization, 2-deoxy-D-glucose, apoptosis, cell proliferation


How to cite this article:
Dwarakanath B S. Cytotoxicity,radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose In vitro. J Can Res Ther 2009;5, Suppl S1:27-31

How to cite this URL:
Dwarakanath B S. Cytotoxicity,radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose In vitro. J Can Res Ther [serial online] 2009 [cited 2019 Jul 18];5:27-31. Available from: http://www.cancerjournal.net/text.asp?2009/5/9/27/55137


 > Introduction Top


Malignant tumors are characterized by higher rates of glucose usage and glycolysis [1] arising on account of malignant transformation, mitochondrial malfunction (linked to or independent of mutations), and microregional hypoxia. Glucose usage generally correlates well with the degree of malignancy and poor prognosis, besides conferring resistance to treatment. [2],[3] Therefore, several approaches to differentially modulate glucose flux and energy supply specifically in cancer are being investigated to improve tumor therapy.

The glucose analog 2-deoxy-D-glucose (2-DG) has been most widely investigated for targeting glucose metabolism and to be developed as a therapeutic agent or adjuvant in cancer therapy. 2-DG competitively inhibits glucose transport and phosphorylation by hexokinase (HK) to form 2-DG-6-phosphate, which is minimally metabolized further, thereby reducing the output from glycolysis (ATP) and the pentose- phosphate pathway (NAPDH). [4],[5],[6],[7],[8] 2-DG has also been shown to induce phosphorylation of Akt via a mechanism independent of LKB1/AMP-activated protein kinase or glycolysis inhibition. [9] Furthermore, 2-DG alters N -linked glycosylation leading to unfolded protein responses and induces changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. [10],[11],[12]

Since cancer cells depend mainly on glucose metabolism for their energy production and macromolecular synthesis, 2-DG has been suggested to inhibit the proliferation of tumor cells and also induce cell death. Many studies have indeed found that 2-DG inhibits the growth of neoplastic cells in vitro . [13],[14],[15],[16],[17],[18],[19] However, inhibition of tumor growth in vivo requires daily administration of 2-DG causing systemic toxicity, thereby limiting its application as a primary therapeutic in the treatment of tumors.

An alternate and more promising approach was suggested by Jain and co-workers for exploiting the inherent differences in glucose metabolism between tumor and normal cells for improving cancer therapy, where 2-DG has been employed as a differential modifier of cellular responses to the widely used therapeutic agents such as radiation and/or cytotoxic drugs. [20],[21] The rationale behind this approach was based on the bioenergetics of cellular damage response pathways including DNA repair, cell proliferation, and cell death on the one hand and enhanced glucose dependence in tumor cells on the other. Several studies using in vitro and in vivo models of tumors have indeed shown that 2-DG selectively sensitizes tumor cells to ionizing radiation, while reducing the damage to normal cells. [21] Since mechanisms underlying cellular responses to damage caused by many anticancer drugs are similar to radiation, it has been suggested that 2-DG has the potential to enhance the efficacy of chemotherapy. [22] Indeed, 2-DG has been found to enhance the damage caused by certain chemotherapeutic drugs in vitro .[23],[24]

This review provides a brief account of 2-DG-induced cytotoxic effects and radio- as well as chemo- sensitization of tumor cells under in vitro conditions.


 > Cytotoxicity Top


The cytotoxic effects of 2-DG are found to be heterogeneous among different tumor cell lines. While profound growth inhibition and cell death have been found in some cells, a marginal effect on growth and clonogenicity have been reported in a few. [13],[14],[15],[16],[17],[18],[19] A number of factors contribute to these two diversified responses that include the extent of glucose dependence and glycolysis, energy deprivation in the form of ATP depletion, [4],[5],[6],[7],[8] and imbalance in the oxidative stress, [19] levels of glucose transporters, c-Myc status, and p53 and p21 status, and the levels of apoptosis-regulating Bcl family of proteins, particularly the Bcl 2 /Bax ratio. [25],[26],[27] Furthermore, the cytotoxic effects of 2-DG are found to be higher under hypoxic conditions and knockdown of HIF-1 significantly enhances the sensitivity of cells under hypoxia to 2-DG, [28],[29] suggesting that inhibition of HIF-1 may improve the clinical efficacy of glycolytic inhibitors such as 2-DG. In line with these observations, 2-DG has been found to be more toxic to tumor cells grown as spheroids (which develop microregions of hypoxia) as compared to monolayer cultures (Khaitan et al. , in this issue).

Cell death induced by 2-DG could be either apoptotic or necrotic depending on the cell type and environmental factors. While the induction of apoptosis has been found in myc overexpressed cells, [18],[26] enhanced apoptotic death has been reported in drug-resistant human carcinoma cells (KB-DR) that could be linked to overexpression of glut receptors induced by 2-DG.[16] Induction of apoptosis independent of Bcl-2 has also been reported recently. [30] Although the cytotoxic effects of 2-DG observed in various human tumor cell lines do not correlate with their p53 status, [18] it appears to be accentuated by higher levels of wild-type p53 as overexpression of p53 has been shown to enhance the apoptotic death of prostate cancer cell lines; PC-3; and DU-145. [31] Susceptibility of p53 overexpressing cells to 2-DG is reduced by higher levels of catalase or glutathione peroxidase suggesting that the mechanism underlying enhanced cell killing by 2-DG in p53 overexpressing cells involves oxidative stress. [31]

The relationship between enhanced glycolysis and apoptotic cell death due to glucose deprivation induced by 2-DG remains to be elucidated, although alteration in the redox state due to a decrease in the regeneration of NADH and lactate by inhibition of glycolysis has been proposed to trigger the final apoptotic pathway. [32] Glucose and oxygen are potent regulators of glycolytic enzyme gene transcripts [33] and therefore, genetic alterations other than c-Myc activation are also expected to sensitize transformed cells to glucose deprivation. Furthermore, glucose by itself stimulates transcription of genes encoding glycolytic enzymes through the carbohydrate response element (ChoRE), a CACGTG motif, [34],[35] which has the same sequence as the core binding site for c-Myc. Whether 2-DG can bind to the ChoRE element with same or higher/ lower efficiency and elicit a similar response is not clear, but is expected to contribute to the glucodeprivation mediated responses.


 > Radiosensitization Top


Several damage response pathways in cells including the repair of DNA lesions require optimal flow of metabolic energy in the form of ATP. 2-DG has been shown to inhibit DNA repair in highly glycolytic cells such as respiratory-deficient mutants of yeast.[36] Since many tumors show enhanced glycolysis and resistance to therapy, several studies have investigated the effects of 2-DG on the cellular responses to radiation and chemotherapeutic drugs in transformed cells under in vitro conditions to evaluate the potential of using 2-DG as an adjuvant for improving the therapeutic efficacy. Extensive studies using many human and murine tumor cell lines have shown that presence of 2-DG added just before (or immediately after) irradiation selectively enhances radiation-induced killing of malignant cells by modifying energy-dependent cellular recovery processes including the repair of DNA damage, cell cycle check points, and apoptosis. [21],[37],[38],[39] 2-DG has also been found to enhance the damage induced by radionuclides alone or coupled with vectors like tumor-specific antibodies and folate.[40],[41] Radiosensitization has also been suggested to be due to disruption of thiol metabolism resulting in oxidative stress-related cell death in the form of apoptosis [42] that could be reduced by the addition of N -acetyl cysteine [43] and enhanced by inhibiting glutamate cysteine ligase activity. [44] Alterations in the expression of many genes involved in damage response pathways including DNA repair and apoptosis, transcriptional regulators, cell signaling, besides energy metabolism have been reported that could significantly influence the radiosensitization of tumor cells.[12] A robust UPR is also induced by 2-DG that contributes to the radiosensitization.[12] The 2-DG-induced enhancement of radiation damage has been found to be directly proportional to the glucose usage, presence of hypoxia, and doses of 2-DG and radiation. [39],[45] Current understanding of the various mechanisms involved in 2-DG-induced cytotoxic effects and radio-/chemosensitization is summarized in [Figure 1].

A great degree of heterogeneity in the 2-DG-induced modifications in radiation responses has been observed among the various human tumor cell lines [39] that does not correlate well with the extent of decrease in the energy status (ATP levels), suggesting thereby that other disturbances caused by 2-DG also play important roles in the modifications of cellular responses to damage caused by radiation and chemotherapeutic drugs. These include (but not restricted to) levels of glucose transporters (glut1 and glut3), prosurvival and prodeath regulators, namely, c-myc, ras, p53, p21, Bcl 2 /Bax ratio, NF-kB, etc., imbalances in the oxidative stress, alterations in UPR responses, and upregulation of VEGF induced by 2-DG.

Variations in the in vivo responses between different types of tumors and heterogeneity among mice bearing the same tumor (EAT) have also prompted studies examining the roles of tumor physiology and host-tumor interactions in the radio- and chemo-sensitization of tumors by 2-DG. Using multicellular tumor spheroids (MTS) as 3D in vitro models of tumors, the influence of tumor physiology on radio- and chemosensitization by 2-DG has been investigated as MTS mimics the microenvironment of tumors including microregions of hypoxia. [45],[46] The degree of radiosensitization by 2-DG in MTS generated from a human glioma cell line (BMG-1) was found to be nearly 2.5-folds higher than in the monolayer cultures (MLC) that correlated with the enhanced glycolysis in MTS. [45] The enhanced sensitivity of MTS was mainly due to a profound induction of apoptosis as compared to cytogenetic damage-linked mitotic death being the major death pathway in MLC. A delayed oxidative stress was observed in spheroids treated with a combination of 2-DG plus radiation that was linked to TNF-α[47] suggesting that the enhanced cell death in spheroids is due to endogenously induced oxidative stress related to TNF-α and radiation-induced oxidative stress synergizing with glucodeprivation-induced oxidative stress arising on account of depletion in pyruvate and lactate, the antioxidants from the glycolytic pathway. These observations also point out the limitations of monolayer cultures that generally lack TNF-α in predicting the effects of 2-DG on tumors under in vivo conditions.

Organ cultures of primary tumor explants preserve the intercellular and cell-matrix interactions present in tumors and provide an excellent model for evaluating tumor response to treatments. Studies on organ cultures of brain tumors have clearly shown that the presence of 2-DG for 2-4h following irradiation enhances radiation-induced cytogenetic damage (micronuclei; reflecting mitotic death) in glioma, meningioma, and schwannoma in a concentration-dependent manner, [48],[49] similar to the results reported in established cell lines.

Analysis of the radiomodifying effects of 2-DG observed in several tumor cell lines reveal that the time of administration of 2-DG with respect to irradiation plays an important role in determining the effects. Sensitization is generally found to be higher when 2-DG added either just before (< 5min) or immediately after (< 5min) irradiation is present in the incubating medium for 2-4h. Since majority of the damage response pathways (particularly DNA repair) induced soon after irradiation is optimally functional for few hours following irradiation, the metabolic perturbations caused by 2-DG (including depletion of energy; ATP) appears to be efficient in enhancing the prodeath pathways and/or reducing the prosurvival pathways (including DNA repair) under these conditions. Therefore, protocols designed based on these in vitro observations will be more effective in providing local tumor control. Since the generation of metabolic oxidative stress induced by 2-DG due to the disruption of thiol metabolism (suggested as another mechanism of action) lasts for several hours and in fact few days following treatment, alternative protocols exploiting this phenomenon may also be useful. It is pertinent to mention here that an inappropriate design of protocols may in fact reduce the efficacy of primary therapeutic agents by 2-DG as has been reported for a combination of radioimmunotherapy and 2-DG under in vivo conditions, [50] although a sensitizing effect of 2-DG has been shown in vitro with radionuclides. [40],[41]


 > Chemosensitization Top


Since Pgp-linked drug efflux as well as biochemical events involved in cellular responses to damage induced by the chemotherapeutic agents is energy dependent, it has been suggested that 2-DG may enhance the damage caused by chemotherapeutic drugs selectively in cancer cells. [22] Furthermore, 2-DG has been shown to inhibit the transcription of human papilloma virus (HPV), suggesting it to be an ideal adjuvant for enhancing the efficacy of chemotherapy in the treatment of drug-resistant cervical cancers. [51]

Treatment of cells with 2-DG following exposure to topoisomerase poisons like camptothecin (topo I inhibitor) and etoposide (Topo II inhibitor) has been found to enhance the cytotoxic effects of these anticancer drugs by increasing both mitotic as well as apoptotic cell death in human glioma and squamous carcinoma cell lines.[23] This increase was accompanied by an accumulation of DNA damage suggesting inhibition of the repair of cleavable complex by 2-DG.[23] 2-DG has also been found to enhance the cytotoxicity of cisplatin, adriamycin, and paclitaxel in prostate, pancreatic, and tumor cell lines. [24],[52] The sensitization of the tumor spheroids (BMG- 1) to etoposide (topoisomerase II inhibitor) has been found to be significantly higher than in monolayer cultures, which was mainly due to a huge increase in the necrotic death.[53] Furthermore, the profound chemosensitization by 2-DG in the spheroids arose from a synergy between endogenous oxidative stresses related to TNF-a, and oxidative stress induced by etoposide as well as glucodeprivation-induced oxidative stress.[54] A marginal decrease in the Pgp level has also been found in tumor spheroids treated with a combination of etoposide and 2-DG, which has been attributed to the oxidative stress-induced degradation of Pgp. [53]


 > Summary and Conclusions Top


The precise molecular mechanisms underlying the cellular responses to metabolic stress induced by 2-DG alone and in combination with other cytotoxic agents like ionizing radiation and chemotherapeutic agents appear to be complex and remain to be completely elucidated. Depletion of energy, induction of oxidative stress, alterations in gene expression, disturbances in cell signaling due to UPR independent and dependent changes in N -linked glycosylation of proteins resulting in mitotic and apoptotic death, inhibition of DNA repair, disturbances in calcium homeostasis, down-regulation of Pgp-mediated drug efflux, perturbations in cell cycle progression, and induction of senescence are some of the contributing factors [Figure 1]. Elucidation of various mechanisms underlying radio- and chemosensitization by 2-DG using established tumor cell lines with diversified biological behavior and with specific genetic manipulations will be very useful in designing effective protocols using 2-DG either as a therapeutic agent or adjuvant.


 > Acknowledgements Top


Research in author's laboratory has been supported by DRDO, Govt. of India.

 
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