Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation
Nùkhet Aykin-Burns, Iman M Ahmad, Yueming Zhu, Larry W Oberley, Douglas R Spitz, Nùkhet Aykin-Burns, Iman M Ahmad, Yueming Zhu, Larry W Oberley, Douglas R Spitz
Abstract
Cancer cells, relative to normal cells, demonstrate increased sensitivity to glucose-deprivation-induced cytotoxicity. To determine whether oxidative stress mediated by O(2)(*-) and hydroperoxides contributed to the differential susceptibility of human epithelial cancer cells to glucose deprivation, the oxidation of DHE (dihydroethidine; for O(2)(*-)) and CDCFH(2) [5- (and 6-)carboxy-2',7'-dichlorodihydrofluorescein diacetate; for hydroperoxides] was measured in human colon and breast cancer cells (HT29, HCT116, SW480 and MB231) and compared with that in normal human cells [FHC cells, 33Co cells and HMECs (human mammary epithelial cells)]. Cancer cells showed significant increases in DHE (2-20-fold) and CDCFH(2) (1.8-10-fold) oxidation, relative to normal cells, that were more pronounced in the presence of the mitochondrial electron-transport-chain blocker, antimycin A. Furthermore, HCT116 and MB231 cells were more susceptible to glucose-deprivation-induced cytotoxicity and oxidative stress, relative to 33Co cells and HMECs. HT29 cells were also more susceptible to 2DG (2-deoxyglucose)-induced cytotoxicity, relative to FHC cells. Overexpression of manganese SOD (superoxide dismutase) and mitochondrially targeted catalase significantly protected HCT116 and MB231 cells from glucose-deprivation-induced cytotoxicity and oxidative stress and also protected HT29 cells from 2DG-induced cytotoxicity. These results show that cancer cells (relative to normal cells) demonstrate increased steady-state levels of ROS (reactive oxygen species; i.e. O(2)(*-) and H(2)O(2)) that contribute to differential susceptibility to glucose-deprivation-induced cytotoxicity and oxidative stress. These studies support the hypotheses that cancer cells increase glucose metabolism to compensate for excess metabolic production of ROS and that inhibition of glucose and hydroperoxide metabolism may provide a biochemical target for selectively enhancing cytotoxicity and oxidative stress in human cancer cells.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2678564/bin/nihms101165f1.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2678564/bin/nihms101165f2.jpg)
![Figure 3. Human breast cancer cells (MB231)…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2678564/bin/nihms101165f3.jpg)
![Figure 4. Clonogenic survival of normal versus…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2678564/bin/nihms101165f4.jpg)
Figure 5. Over expression of MnSOD and…
Figure 5. Over expression of MnSOD and mitoCAT in HCT116 and MB231 cells suppressed the…
Figure 6. Toxicity of 20 mM 2DG…
Figure 6. Toxicity of 20 mM 2DG in normal (FHC) cells (A) vs cancer (HT29)…
- Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells.Fath MA, Diers AR, Aykin-Burns N, Simons AL, Hua L, Spitz DR. Fath MA, et al. Cancer Biol Ther. 2009 Jul;8(13):1228-36. doi: 10.4161/cbt.8.13.8631. Epub 2009 Jul 6. Cancer Biol Ther. 2009. PMID: 19411865 Free PMC article.
- Mitochondrial O2*- and H2O2 mediate glucose deprivation-induced stress in human cancer cells.Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, Venkataraman S, Mackey MA, Flanagan SW, Oberley LW, Spitz DR. Ahmad IM, et al. J Biol Chem. 2005 Feb 11;280(6):4254-63. doi: 10.1074/jbc.M411662200. Epub 2004 Nov 23. J Biol Chem. 2005. PMID: 15561720
- Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress.Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM, Spitz DR. Hadzic T, et al. Free Radic Biol Med. 2010 Apr 15;48(8):1024-33. doi: 10.1016/j.freeradbiomed.2010.01.018. Epub 2010 Jan 18. Free Radic Biol Med. 2010. PMID: 20083194 Free PMC article.
- Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism.Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. Allen BG, et al. Redox Biol. 2014;2:963-70. doi: 10.1016/j.redox.2014.08.002. Epub 2014 Aug 7. Redox Biol. 2014. PMID: 25460731 Free PMC article. Review.
- Glucose deprivation-induced metabolic oxidative stress and cancer therapy.Simons AL, Mattson DM, Dornfeld K, Spitz DR. Simons AL, et al. J Cancer Res Ther. 2009 Sep;5 Suppl 1(Suppl 1):S2-6. doi: 10.4103/0973-1482.55133. J Cancer Res Ther. 2009. PMID: 20009288 Free PMC article. Review.
- Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review.Mikolaskova I, Crnogorac-Jurcevic T, Smolkova B, Hunakova L. Mikolaskova I, et al. Biology (Basel). 2023 Jan 19;12(2):158. doi: 10.3390/biology12020158. Biology (Basel). 2023. PMID: 36829437 Free PMC article. Review.
- Chemical Composition and Biological Activity of Tanacetum balsamita Essential Oils Obtained from Different Plant Organs.Vukic MD, Vukovic NL, Obradovic AD, Galovičová L, Čmiková N, Kačániová M, Matic MM. Vukic MD, et al. Plants (Basel). 2022 Dec 12;11(24):3474. doi: 10.3390/plants11243474. Plants (Basel). 2022. PMID: 36559586 Free PMC article.
- Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.Shimada BK, Swanson S, Toh P, Seale LA. Shimada BK, et al. Biomolecules. 2022 Oct 28;12(11):1581. doi: 10.3390/biom12111581. Biomolecules. 2022. PMID: 36358931 Free PMC article. Review.
- Pharmacological and Therapeutic Applications of Esculetin.Garg SS, Gupta J, Sahu D, Liu CJ. Garg SS, et al. Int J Mol Sci. 2022 Oct 20;23(20):12643. doi: 10.3390/ijms232012643. Int J Mol Sci. 2022. PMID: 36293500 Free PMC article. Review.
- NOX as a Therapeutic Target in Liver Disease.Matuz-Mares D, Vázquez-Meza H, Vilchis-Landeros MM. Matuz-Mares D, et al. Antioxidants (Basel). 2022 Oct 16;11(10):2038. doi: 10.3390/antiox11102038. Antioxidants (Basel). 2022. PMID: 36290761 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Cell Line
- Cell Survival / drug effects
- Glucose / metabolism
- Glucose / pharmacology*
- Glucosephosphate Dehydrogenase / metabolism
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- NADP / metabolism
- Neoplasms / metabolism*
- Neoplasms / pathology
- Oxidation-Reduction
- Superoxides / metabolism*
- Superoxides
- NADP
- Hydrogen Peroxide
- Glucosephosphate Dehydrogenase
- Glucose
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![Figure 5. Over expression of MnSOD and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2678564/bin/nihms101165f5.jpg)
Figure 6. Toxicity of 20 mM 2DG…
Figure 6. Toxicity of 20 mM 2DG in normal (FHC) cells (A) vs cancer (HT29)…
- Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells.Fath MA, Diers AR, Aykin-Burns N, Simons AL, Hua L, Spitz DR. Fath MA, et al. Cancer Biol Ther. 2009 Jul;8(13):1228-36. doi: 10.4161/cbt.8.13.8631. Epub 2009 Jul 6. Cancer Biol Ther. 2009. PMID: 19411865 Free PMC article.
- Mitochondrial O2*- and H2O2 mediate glucose deprivation-induced stress in human cancer cells.Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, Venkataraman S, Mackey MA, Flanagan SW, Oberley LW, Spitz DR. Ahmad IM, et al. J Biol Chem. 2005 Feb 11;280(6):4254-63. doi: 10.1074/jbc.M411662200. Epub 2004 Nov 23. J Biol Chem. 2005. PMID: 15561720
- Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress.Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM, Spitz DR. Hadzic T, et al. Free Radic Biol Med. 2010 Apr 15;48(8):1024-33. doi: 10.1016/j.freeradbiomed.2010.01.018. Epub 2010 Jan 18. Free Radic Biol Med. 2010. PMID: 20083194 Free PMC article.
- Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism.Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. Allen BG, et al. Redox Biol. 2014;2:963-70. doi: 10.1016/j.redox.2014.08.002. Epub 2014 Aug 7. Redox Biol. 2014. PMID: 25460731 Free PMC article. Review.
- Glucose deprivation-induced metabolic oxidative stress and cancer therapy.Simons AL, Mattson DM, Dornfeld K, Spitz DR. Simons AL, et al. J Cancer Res Ther. 2009 Sep;5 Suppl 1(Suppl 1):S2-6. doi: 10.4103/0973-1482.55133. J Cancer Res Ther. 2009. PMID: 20009288 Free PMC article. Review.
- Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review.Mikolaskova I, Crnogorac-Jurcevic T, Smolkova B, Hunakova L. Mikolaskova I, et al. Biology (Basel). 2023 Jan 19;12(2):158. doi: 10.3390/biology12020158. Biology (Basel). 2023. PMID: 36829437 Free PMC article. Review.
- Chemical Composition and Biological Activity of Tanacetum balsamita Essential Oils Obtained from Different Plant Organs.Vukic MD, Vukovic NL, Obradovic AD, Galovičová L, Čmiková N, Kačániová M, Matic MM. Vukic MD, et al. Plants (Basel). 2022 Dec 12;11(24):3474. doi: 10.3390/plants11243474. Plants (Basel). 2022. PMID: 36559586 Free PMC article.
- Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.Shimada BK, Swanson S, Toh P, Seale LA. Shimada BK, et al. Biomolecules. 2022 Oct 28;12(11):1581. doi: 10.3390/biom12111581. Biomolecules. 2022. PMID: 36358931 Free PMC article. Review.
- Pharmacological and Therapeutic Applications of Esculetin.Garg SS, Gupta J, Sahu D, Liu CJ. Garg SS, et al. Int J Mol Sci. 2022 Oct 20;23(20):12643. doi: 10.3390/ijms232012643. Int J Mol Sci. 2022. PMID: 36293500 Free PMC article. Review.
- NOX as a Therapeutic Target in Liver Disease.Matuz-Mares D, Vázquez-Meza H, Vilchis-Landeros MM. Matuz-Mares D, et al. Antioxidants (Basel). 2022 Oct 16;11(10):2038. doi: 10.3390/antiox11102038. Antioxidants (Basel). 2022. PMID: 36290761 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Cell Line
- Cell Survival / drug effects
- Glucose / metabolism
- Glucose / pharmacology*
- Glucosephosphate Dehydrogenase / metabolism
- Health*
- Humans
- Hydrogen Peroxide / metabolism*
- NADP / metabolism
- Neoplasms / metabolism*
- Neoplasms / pathology
- Oxidation-Reduction
- Superoxides / metabolism*
- Superoxides
- NADP
- Hydrogen Peroxide
- Glucosephosphate Dehydrogenase
- Glucose
- F32 CA110611/CA/NCI NIH HHS/United States
- P30 CA086862/CA/NCI NIH HHS/United States
- R01 CA115438/CA/NCI NIH HHS/United States
- R01-CA100045/CA/NCI NIH HHS/United States
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![Figure 6. Toxicity of 20 mM 2DG…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2678564/bin/nihms101165f6.jpg)
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