Anticancer and Radiosensitization Efficacy of Nanocomposite Withania somnifera Extract in Mice Bearing Tumor Cells

  • Abdallah, Nadia M (Department of Biochemistry, Faculty of Science, Ain Shams University) ;
  • Noaman, Eman (Department of Radiation biology, National Center for Radiation Research and Technology, (NCRRT), Egyptian Atomic Energy Authority (EAEA)) ;
  • Eltahawy, Noaman A (Department of Radiation biology, National Center for Radiation Research and Technology, (NCRRT), Egyptian Atomic Energy Authority (EAEA)) ;
  • Badawi, Abdelfattah M (Petrochemical Department, Egyptian Petroleum Research Institute) ;
  • Kandil, Eman (Department of Biochemistry, Faculty of Science, Ain Shams University) ;
  • Mansour, NA (Petrochemical Department, Egyptian Petroleum Research Institute) ;
  • Mohamed, Hebatallah E (Department of Radiation biology, National Center for Radiation Research and Technology, (NCRRT), Egyptian Atomic Energy Authority (EAEA))
  • Published : 2016.09.01

Abstract

The objective of the present study was to evaluate the anticancer and radio-sensitizing efficacy of a Withania somnifera extract/Gadolinium III oxide nanocomposite (WSGNC) in mice. WSGNC was injected to solid Ehrlich carcinoma-bearing mice via i.p. (227 mg/kg body weight) 3 times/week during 3 weeks. Irradiation was performed by whole body fractionated exposure to 6Gy, applied in 3 doses of 2 Gy/week over 3 weeks. Biochemical analyses as well as DNA fragmentation were performed. Treatment of solid Ehrlich carcinoma bearing mice with WSGNC combined with ${\gamma}$-radiation led to a significant decrease in the tumor size and weight associated with a significant decrease in mitochondrial enzyme activities, GSH content and SOD activity as well as a significant increase in caspase-3 activity, MDA concentration and DNA fragmentation in cancer tissues. Combined treatment of WSGNC and low dose of ${\gamma}$-radiation showed great amelioration in lipid peroxidation and antioxidant status (GSH content and SOD activity) in liver tissues in animals bearing tumors. It is concluded that WSGNC can be considered as a radio-sensitizer and anticancer modulator, suggesting a possible role in reducing the radiation exposure dose during radiotherapy.

Keywords

References

  1. Aghamohammadi A, Hosseinimehr SJ, Ghasemi A, et al (2015). Radiosensitization effects of a Zataria multiflora extract on human glioblastoma cells. Asian Pac J Cancer Prev, 16, 7285-90. https://doi.org/10.7314/APJCP.2015.16.16.7285
  2. Akhila JS, Deepa S, Alwar MC (2007). Acute toxicity studies and determination of median lethal dose. J Curr Sci, 93, 917-20.
  3. Ansari AQ, Ahmed SA, Waheed MA, et al (2013). Extraction and determination of antioxidant activity of Withania somnifera Dunal. Eur J Experimental Biol, 3, 502-7.
  4. Arora MS, (2008). Herbal Radiomodulators, Applications in Medicine, Home and Defence & Space. Edited By Rajesh Arora, Cabi International, Biddlesltd, Kings Lynn.
  5. Aurelio M, Gajewski CD, Lenaz G, et al (2006). Respiratory chain supercomplexes set the threshold for respiratory defects in human mtDNA mutant cybrids. J Hum Mol Genet, 15, 2157-69. https://doi.org/10.1093/hmg/ddl141
  6. Basha R, Sabnis N, Heym K, et al (2014). Targeted nanoparticles for pediatric leukemia therapy. J Front Oncol, 13, 101.
  7. Bhaskar M, Chintamaneni M, (2014).Withania somnifera and eclipta alba ameliorate oxidative stress induced mitochondrial dysfunction in an animal model of alzheimer's disease. Am J Phytomedicine Clinical Therapeutics, 2, 140-52.
  8. Bras LM, Clement MV, Pervaiz S, et al (2005). Reactive oxygen species and the mitochondrial signaling pathway of cell death. J Histol Histopathol, 20, 205-19.
  9. Barrera G, (2012). Oxidative Stress and Lipid Peroxidation Products in Cancer Progression and Therapy. J ISRN Oncol, 137289, 21.
  10. Beutler E, Duron O, and Kelly MB, (1963). Improved method for the determination of blood glutathione. J Lab Clin Med, 61, 882-88.
  11. Ceresa C, Bravin A, Cavaletti, G, et al (2014). The combined therapeutical effect of metal-based drugs and radiation therapy: the present status of research. J Curr Med Chem, 21, 2237-65. https://doi.org/10.2174/0929867321666140216125721
  12. Cho S, Lee Y, Lee S, et al (2014). Enhanced cytotoxic and genotoxic effects of gadolinium following ELF-EMF irradiation in human lymphocytes. J Drug Chem Toxicol, 37, 440-7. https://doi.org/10.3109/01480545.2013.879662
  13. Christina AJM, Joseph DG, Packialakshmi M, et al (2004). Anticarcinogenic activity of withania somnifera dunal against daltons ascitic lymploma. J Ethnopharmacol, 93, 359-61. https://doi.org/10.1016/j.jep.2004.04.004
  14. Cui ZG, Piao JL, Rehman MU, et al (2014). Molecular mechanisms of hyperthermia-induced apoptosis enhanced by withaferin A. Eur J Pharmacol, 15, 99-107.
  15. David M. Euhus MD, Charles Hudd MB, et al (1986).Tumor measurement in the nude mouse. J Surgical Oncol, 31, 229-34. https://doi.org/10.1002/jso.2930310402
  16. Ekert PG, Silke J, Vaux DL, (1999). Caspase inhibitor. J Cell Death Differ, 6, 1081-86. https://doi.org/10.1038/sj.cdd.4400594
  17. Fruehauf JP, Meyskens FL, (2007). Reactive oxygen species: a breath of life or death? J Cin Cancer Res, 13, 789-94. https://doi.org/10.1158/1078-0432.CCR-06-2082
  18. Hahm ER, Moura MB, Kelley EE, et al (2011). Withaferin A-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species. J PLoS One, 6, 23354. https://doi.org/10.1371/journal.pone.0023354
  19. Hamburger AW, (1981). Use of in-vitro testes in predictive cancer chemotherapy. J NCI, 66, 981.
  20. Hematulin A, Ingkaninan K, Limpeanchob N, et al (2014). Ethanolic extract from Derris scandens Benth mediates radiosensitzation via two distinct modes of cell death in human colon cancer HT-29 cells. Asian Pac J Cancer Prev, 15, 1871-77. https://doi.org/10.7314/APJCP.2014.15.4.1871
  21. Henze K, Martin W, Martin W, (2003). "Evolutionary biology: essence of mitochondria". J Nature, 426, 127-8. https://doi.org/10.1038/426127a
  22. Jensen MM, Jorgensen J, Binderu PT, et al (2008). Tumour volume in subcutaneous mouse xenografts measured by micro CT is more is more accurate and reproducible than determined by F-FDG-micro PET or external caliper. J BMC Medical Imaging, 8, 16 https://doi.org/10.1186/1471-2342-8-16
  23. Johansson LH, Borg, LA, (1988): A spectrophotometric method for determination of catalase activity in small tissue samples. J Anal Biochem, 174, 331-36. https://doi.org/10.1016/0003-2697(88)90554-4
  24. Josson S, Xu Y, Fang F, et al (2005). RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells. J Oncogene, 25, 1554-59.
  25. Khazal KF, Simon L, Odemuyiwa S, et al (2013).Withania somnifera extract inhibits invasion and metastasis of MDAMB-231 cells by inhibiting CCL2 and CD44 high/CD24low stem cells. J Res, 73.
  26. Kroemer G, Galluzzi L, Vandenabeele P, et al (2009). Classification of cell death: recommendations of the nomenclature committee on cell death. J Cell Death Differ, 16, 3-11. https://doi.org/10.1038/cdd.2008.150
  27. Kwatra D, Venugopa A, Anant S, (2013). Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer. J Transl Cancer Res, 2, 330-42.
  28. Kwong k, Sohal RS, (2000). Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse. J Arch Biochem Biophs, 307, 16-22.
  29. Lee DH, Lim, IH, Sung EG, et al (2013). Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway. J Oncol Rep, 30, 933-38. https://doi.org/10.3892/or.2013.2487
  30. Lee WH, Loo CY, Young PM, et al (2014).Recent advances in curcumin nanoformulation for cancer therapy. J Expert Opin Drug Deliv, 24, 1-19.
  31. Maliyakkal N, Udupa N, Pai KSR, et al (2013). Cytotoxic and apoptotic activities of extracts of Withania somnifera and Tinosporacordifolia in human breast cancer cells. Int J Applied Research in Natural Products, 6, 1-10.
  32. Mansour HH, Hafez HF, (2012). Protective effect of Withania somnifera against radiation-induced hepatotoxicity in rats. J Ecotoxicology Environmental Safety, 80, 14-19. https://doi.org/10.1016/j.ecoenv.2012.02.003
  33. Mayola E, Gallerne C, Espoti DD, et al (2011). Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species. J Apoptosis, 16, 1014-27. https://doi.org/10.1007/s10495-011-0625-x
  34. Miladi I, Aloy MT, Armandy E, et al (2015). Combining ultrasmall gadolinium-based nanoparticles with photon irradiation overcomes radioresistance of head and neck squamous cell carcinoma. J Nanomedicine, 11, 247-57. https://doi.org/10.1016/j.nano.2014.06.013
  35. Narang AS, Desai DS, (2009). Anticancer drug development unique aspects of pharmaceutical development. Y. LU, R. I. Mahato (eds), pharmaceutical perspectives of cancer therapeutics, 49-92.
  36. Okamura T, Miura T, Takemura G, et al (2000). Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. J Cardiovascular Res, 45, 642-50. https://doi.org/10.1016/S0008-6363(99)00271-0
  37. Park JW, Min KT J, Kim DE, et al (2015). Withaferin A induces apoptosis through the generation of thiol oxidation in human head and neck cancer cells. Int J Mol Med, 35, 247-52. https://doi.org/10.3892/ijmm.2014.1983
  38. Porter AG, Janicke RU, (1999). Emerging role of caspase-3 in apoptosis (review). J Cell Death Differ, 6, 99-104. https://doi.org/10.1038/sj.cdd.4400476
  39. Raviraj J, Bokkasam VK, Kumar et al (2014). Radiosensitizers, radioprotectors, and radiation mitigators. Ind J Dent Res, 25, 83-90. https://doi.org/10.4103/0970-9290.131142
  40. Rickwood D, Wilson, MT, Darley-Usmar V M, (1978). Isolation and characteristic of intact mitochondria In: V. M. Darley-Usmar, D. Rickwood, M. T. Wilson, (eds). Mitochondria: A practical approach. I. R. L. press, Washington, D. C. pp 4-5.
  41. Roblero-Bartolon GV, Ramon-Gallegos E, (2015). Use of nanoparticles (NP) in photodynamic therapy (PDT) against cancer. J Gac Med Mex, 151, 85-98.
  42. Senthil K, Jayakodi M, Thirugnanasambantham P, et al (2015). Transcriptome analysis reveals in vitro cultured Withania somnifera leaf and root tissues as a promising source for targeted withanolide biosynthesis. J BMC Genomics, 22, 14.
  43. Sharma LK, Lu J, Bai Y, (2009). Mitochondrial respiratory complex I: structure, function and implication in human diseases. J Curr Med Chem, 16, 1266-77. https://doi.org/10.2174/092986709787846578
  44. Sinha P, Ostrand-Rosenberg S, (2013). Myeloid-derived suppressor cell function is reduced by Withaferin A, a potent and abundant component of Withaniasomnifera root extract. J Cancer Immunol Immunother, 27, 1663-73.
  45. Sun Y, Oberley LW, Li Y, (1988). A simple method for clinical assay of superoxide dismutase. J Clin Chem, 34, 497-500.
  46. Tiwari R, Chakraborty S, Saminathan M, et al (2014). Ashwagandha (Withania somnifera): Role in safeguarding health, immunomodulatory effects, combating infections and therapeutic applications: A review. J Biological Sciences, 14, 77-94. https://doi.org/10.3923/jbs.2014.77.94
  47. Unsoy G, Yalcin S, Khodadust R, et al (2014). Chitosan magnetic nanoparticles for pH responsive Bortezomibrelease in cancer therapy. J Biomed Pharmacother, 68, 641-8. https://doi.org/10.1016/j.biopha.2014.04.003
  48. Wallace DC, (2008). Mitochondria as chi. J Genetics, 179, 727-35. https://doi.org/10.1534/genetics.104.91769
  49. Wang T, Zhang X, Li JJ, (2002). The role of NF-${\kappa}B$ in the regulation of cell stress responses. Int J Immunopharmacol, 2, 1509-20. https://doi.org/10.1016/S1567-5769(02)00058-9
  50. Wanger H, Bladt S, Zagaiwski EM, (Eds.) (1984). Plant drug analysis. Springer-verlag, Berlin/New YORK, PP. 126-169
  51. Wilson JK, Sargent JM, Elgie AW, et al (1990). A feasibility for chemosensitivity testing in ovarian malignancy. Br J Cancer, 2, 189-194.
  52. Yang ES, Choi MJ, Kim JH, et al (2011). Withaferin A enhances radiation- induced apoptosis in Caki cells through induction of reactive oxygen species, Bcl-2 downregulation and Akt inhibition. Chem-Biol Interact, 190, 9-15. https://doi.org/10.1016/j.cbi.2011.01.015
  53. Yoshioka T, Kawada K, Shimada T, et al (1979). Lipid peroxidation in maternal and cord blood and protective mechanism against activated oxygen toxicity in the blood. Am J Obstet Gynec, 135, 372-76. https://doi.org/10.1016/0002-9378(79)90708-7
  54. Zhang X, Zhou X, Chen, R, et al (2012). Radiosensitization by inhibiting complex I activity in human hepatoma HepG2 cells to X-ray radiation. J Radiat Res, 53, 257-63. https://doi.org/10.1269/jrr.11124