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Combined Treatment with 2-Deoxy-D-Glucose and Doxorubicin Enhances the in Vitro Efficiency of Breast Cancer Radiotherapy

  • Islamian, Jalil Pirayesh (Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences) ;
  • Aghaee, Fahimeh (Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences) ;
  • Farajollahi, Alireza (Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences) ;
  • Baradaran, Behzad (Immunology Research center, Faculty of Medicine, Tabriz University of Medical Sciences) ;
  • Fazel, Mona (Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences)
  • Published : 2016.01.11

Abstract

Doxorubicin (DOX) was introduced as an effective chemotherapeutic for a wide range of cancers but with some severe side effects especially on myocardia. 2-Deoxy-D-glucose (2DG) enhances the damage caused by chemotherapeutics and ionizing radiation (IR) selectively in cancer cells. We have studied the effects of $1{\mu}M$ DOX and $500{\mu}M$ 2DG on radiation induced cell death, apoptosis and also on the expression levels of p53 and PTEN genes in T47D and SKBR3 breast cancer cells irradiated with 100, 150 and 200 cGy x-rays. DOX and 2DG treatments resulted in altered radiation-induced expression levels of p53 and PTEN genes in T47D as well as SKBR3 cells. In addition, the combination along with IR decreased the viability of both cell lines. The radiobiological parameter (D0) of T47D cells treated with 2DG/DOX and IR was 140 cGy compared to 160 cGy obtained with IR alone. The same parameters for SKBR3 cell lines were calculated as 120 and 140 cGy, respectively. The sensitivity enhancement ratios (SERs) for the combined chemo-radiotherapy on T47D and SKBR3 cell lines were 1.14 and 1.16, respectively. According to the obtained results, the combination treatment may use as an effective targeted treatment of breast cancer either by reducing the single modality treatment side effects.

Keywords

References

  1. Aft RL, Zhang FW, and Gius D (2002). Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. Br J Cancer, 87, 805-12. https://doi.org/10.1038/sj.bjc.6600547
  2. Aghaee F, Pirayesh Islamian J, Baradaran B (2012). Enhanced radiosensitivity and chemosensitivity of breast cancer cells by 2-deoxy-d-glucose in combination therapy. J Breast Cancer, 15, 141-7. https://doi.org/10.4048/jbc.2012.15.2.141
  3. Aghaee F, Pirayesh Islamian J, Baradaran B, et al (2013). Enhancing the radiation induced apoptosis in T47D and SKBR3 breast cancer cells by a low dose doxorubicin treatment. J Breast Cancer, 16, 164-70. https://doi.org/10.4048/jbc.2013.16.2.164
  4. Ahmad I, Mustafa EH, Mustafa NH, et al (2010). 2DG enhances the susceptibility of breast cancer cells to doxorubicin. Open Life Sci, 5, 739-48.
  5. Andringa KK, Coleman MC, Aykin-Burns N, et al (2006). Inhibition of glutamate cysteine ligase (GCL) activity sensitizes human breast cancer cells to the toxicity of 2-deoxy-D-glucose. Cancer Res, 66, 1605-10. https://doi.org/10.1158/0008-5472.CAN-05-3462
  6. Aykin-Burns N, Ahmad IM, Zhu Y, et al (2009). Increased levels of superoxide and $H_2O_2$ mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J, 418, 29-37. https://doi.org/10.1042/BJ20081258
  7. Bergh J, Jonsson PE, Glimelius B, et al (2001). Swedish council of technology assessment in Health Care. A systematic overview of chemotherapy effects in breast cancer. Acta Oncol, 40, 253-81. https://doi.org/10.1080/02841860120784
  8. Butt AJ, Firth SM, King MA, et al (2000). Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J BiolChem, 275, 39174-81.
  9. Cao J, Cui S, Li S, et al (2013). Targeted cancer therapy with a 2-deoxyglucose-based adriamycin complex. Cancer Res, 73, 1362-73. https://doi.org/10.1158/0008-5472.CAN-12-2072
  10. Carter SK (1979). CROS conference on combined modalities chemotherapy/radiotherapy. cancer chemother Pharmacolo, 2, 139-42.
  11. Chabner BA, Ryan DP, Paz-Ares L, et al (2001). Antineoplastic agents. In 'The Pharmacological Basis of Therapeutics', Eds Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman's. 10th Ed. New York: McGraw-Hill Medical Publishing Division, 1389-99.
  12. Coleman MC, Asbury CR, Daniels D, et al (2008). 2-Deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer. Free Radic Biol Med, 44, 322-31. https://doi.org/10.1016/j.freeradbiomed.2007.08.032
  13. Dwarakanath BS, Jain VK (1987). Modification of the radiation induced damage by 2-deoxy-D-glucose in organ cultures of human cerebral gliomas. Int J Radiat Oncol Biol Phys, 13, 741-6. https://doi.org/10.1016/0360-3016(87)90293-8
  14. Dwarakanath BS (2009). Cytotoxicity, radiosensitization and chemosensitization of tumor cells by 2-deoxy-D-glucose in vitro. J Cancer Ref Ther, 5, 27-31. https://doi.org/10.4103/0973-1482.55137
  15. Dwarkanath BS, Zolzer F, Chandana S, et al (2001). Heterogeneity in 2-deoxy-D-glucose-induced modifications in energetics and radiation responses of human tumor cell lines. Int J Radiat Oncol Biol Phys, 50, 1051-61. https://doi.org/10.1016/S0360-3016(01)01534-6
  16. Esposito F, Chirico G, Montesano Gesualdi N, et al (2003). Protein kinase B activation by reactive oxygen species is independent of tyrosine kinase receptor phosphorylation and requires SRC activity. J Biol Chem, 278, 20828-34. https://doi.org/10.1074/jbc.M211841200
  17. Ghilotti M, Pierotti MA, Gariboldi M (2010). Molecular markers for prediction of risk of radiation-related injury to normal tissue. J Nucleic Acids Investig, 1, 55-61.
  18. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN (2007). Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol, 608, 1-22. https://doi.org/10.1007/978-0-387-74039-3_1
  19. Gupta S, Farooque A, Adhikari JS, et al (2009). Enhancement of radiation and chemotherapeutic drug responses by 2-deoxy-D-glucose in animal tumors. J Cancer Res Ther, 5, 16-20. https://doi.org/10.4103/0973-1482.55135
  20. Heminger K, Jain V, Kadakia M, et al (2006). Altered gene expression induced by ionizing radiation and glycolytic inhibitor 2-deoxy-glucose in a human glioma cell line: Implications for radiosensitization. Cancer Biol Ther, 5, 815-23. https://doi.org/10.4161/cbt.5.7.2812
  21. Hollestelle A, Elstrodt F, Nagel JH, et al (2007). Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res, 5, 195-201. https://doi.org/10.1158/1541-7786.MCR-06-0263
  22. Hortobagyi GN (1997). Anthracyclines in the treatment of cancer:An overview. Drugs, 54, 1-7.
  23. Jain VK, Purohit SC, Pohlit W (1977). Optimization of cancer therapy: Part I. Inhibition of repair of X-ray induced potentially lethal damage by 2-Deoxy-D-Glucose in Ehrlich ascites tumour cells. Indian J Exp Biol, 15, 711-3.
  24. Ju GZ, Shen B, Sun SL, et al (2007). Effect of X-rays on expression of caspase-3 and p53 in EL-4 cells and its biological implications. Biomed Environ Sci, 20, 456-9.
  25. Kaabinejadian S, Azizi E (2008). P53 Expression in MCF7, T47D and MDA-MB 468 breast cancer cell lines treated with adriamycin using RT-PCR and immunocytochemistry. J Biol Sci, 8, 380-5. https://doi.org/10.3923/jbs.2008.380.385
  26. Kalia VK, Devi NK (1994). Differential modification of radiation damage in 5-bromo-2-deoxy-uridine sensitized human glioma cells and PHA-stimulated peripheral leukocytes by 2-Deoxy-D-Glucose. Indian J Exp Biol, 32, 637-42.
  27. Kalia VK, Prabhakara S, Narayanan V (2009). Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy. J Cancer Res Ther, 5, 57-60. https://doi.org/10.4103/0973-1482.55145
  28. Kalia VK (1999). Optimizing radiation therapy of brain tumors by combination of 5-bromo-2-deoxy-uridine and 2-deoxy-D-glucose. Indian J Med Res, 109, 182-7.
  29. Kerr JF, Winterford CM, Harmon BV (1994). Apoptosis: Its significance in cancer and cancer therapy. Cancer, 73, 2013-26. https://doi.org/10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J
  30. Khaitan D, Chandna S, Arya MB, et al (2006). Differential mechanisms of radiosensitization by 2-Deoxy-D-Glucose in the monolayers and multicellular spheroids of a human glioma cell line. Cancer Biol Ther, 5, 1142-51. https://doi.org/10.4161/cbt.5.9.2986
  31. Lee YJ, Galoforo SS, Berns CM, et al (1998). Glucose deprivation-induced cytotoxicity and alterations in mitogenactivated protein kinase activation are mediated by oxidative stress in multidrug-resistant human breast carcinoma cells. J Biol Chem, 273, 5294-9. https://doi.org/10.1074/jbc.273.9.5294
  32. Lin X, Zhang F, Bradbury CM, et al (2003). 2-Deoxy-D-Glucoseinduced Cytotoxicity and Radiosensitization in Tumor Cells Is Mediated via Disruptions in Thiol Metabolism. Cancer Res, 63, 3413-7.
  33. Lu X, Nannenga B, Donehower LA (2005). PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev, 19, 1162-74. https://doi.org/10.1101/gad.1291305
  34. Maher JC, Krishan A, Lampidis TJ (2004). Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol, 53, 116-22. https://doi.org/10.1007/s00280-003-0724-7
  35. Meek WD (2004). The p53 response to DNA damage. DNA Repair, 3, 1049-56. https://doi.org/10.1016/j.dnarep.2004.03.027
  36. Mohanti BK, Rath GK, Anantha N, et al (1996). Improving cancer radiotherapy with 2-deoxy-D-glucose: Phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys, 35, 103-11.
  37. Moulder S, Hortobagyi GN (2008). Advances in the treatment of breast cancer. Clin Pharmacol Ther, 83, 26-36. https://doi.org/10.1038/sj.clpt.6100449
  38. Mustafa EH, Mahmoud HT, Al-Hudhud MY, et al (2015). 2-deoxy-D-Glucose synergizes with doxorubicin or L-buthionine sulfoximine to reduce adhesion and migration of breast cancer cells. Asian Pac J Cancer Prev, 16, 3213-22. https://doi.org/10.7314/APJCP.2015.16.8.3213
  39. Nakamura Y (2004). Isolation of p53-target genes and their functional analysis. Cancer Sci, 95, 7-11. https://doi.org/10.1111/j.1349-7006.2004.tb03163.x
  40. O'Shaughnessy J (2003). Liposomal anthracyclines for breast cancer: Overview. Oncologist, 8, 1-2.
  41. Pelicano H, Martin DS, Xu RH, et al (2006). Glycolysis inhibition for anticancer treatment. Oncogene, 25, 4633-46. https://doi.org/10.1038/sj.onc.1209597
  42. Sasaki A, Udaka Y, Tsunoda Y, et al (2012). Analysis of p53 and miRNA expression after irradiation of glioblastoma cell lines. Anticancer Res, 32, 4709-13.
  43. Simons AL, Ahmad IM, Mattson DM, et al (2007). 2-Deoxy-Dglucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res, 67, 3364-70. https://doi.org/10.1158/0008-5472.CAN-06-3717
  44. Singh G, Lakkis CL, Laucirica R, et al (1999). Regulation of prostate cancer cell division by glucose. J Cell Physiol, 180, 431-8. https://doi.org/10.1002/(SICI)1097-4652(199909)180:3<431::AID-JCP14>3.0.CO;2-O
  45. Sinthupibulyakit C, Grimes KR, Domann FE, et al (2009). p53 is an important factor for the radiosensitization effect of 2-deoxy-D-glucose. Int J Oncol, 35, 609-15.
  46. Spitz DR, Sim JE, Ridnour LA, et al (2000). Glucose deprivationinduced oxidative stress in human tumor cells. A fundamental defect in metabolism? Ann N Y Acad Sci, 899, 349-62.
  47. Streffer C, Beuningen V, Gross E, et al (1986). Predictive assays for the therapy of rectum carcinoma. Radiother Oncol, 5, 303-10. https://doi.org/10.1016/S0167-8140(86)80179-7
  48. Tan ML, Choong PF, Dass CR (2009). Review: Doxorubicin delivery systems based on chitosan for cancer therapy. J Pharm Pharmacol, 61, 131-42. https://doi.org/10.1211/jpp.61.02.0001
  49. Tewey KM, Rowe TC, Yang L, et al (1984). Adriamycin induced DNA damage mediated by mammalian DNA topoisomerase II. Science, 226, 466-8. https://doi.org/10.1126/science.6093249
  50. Wang SY, Wei YH, Shieh DB, et al (2015). 2-Deoxy-d-Glucose can complement doxorubicin and sorafenib to suppress the growth of papillary thyroid carcinoma cells. PLoS One, 10, 130959.
  51. Zhang F, Aft RL (2009). Chemosensitizing and cytotixic effect of 2-deoxy-D-glucose on breast cancer cells. J Cancer Res Ther, 5, 41-3.
  52. Zhuang HQ, Wang J, Yuan ZY, et al (2009). The drug-resistance to gefitinib in PTEN low expression cancer cells is reversed by irradiation in vitro. J Exp Clin Cancer Res, 28, 123. https://doi.org/10.1186/1756-9966-28-123

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