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Tumor Biology

, Volume 37, Issue 8, pp 11025–11038 | Cite as

Crystal structure and chemotherapeutic efficacy of the novel compound, gallium tetrachloride betaine, against breast cancer using nanotechnology

  • Ahmed Salem
  • Eman Noaman
  • Eman kandil
  • Abdelfattah Badawi
  • Nihal Mostafa
Original Article

Abstract

The objective of this study was to investigate the antitumor efficacy of a novel synthesized compound, betaine gallium-tetrachloride (BTG), alone or combined with ZnO-nanoparticles (BTG + ZnO-NPs) on the incidence of 7, 12-dimethylbenz-anthrathene-induced mammary tumor in female rats. Crystal and molecular structure of the prepared BTG were identified using X-ray crystallography. In vitro study revealed BTG more cytotoxic than BTG + ZnO-NPs on human breast cancer (MCF-7) cell line. In vivo study demonstrated that the blood antioxidant status of tumor-bearing rats (DMBA group) was significantly lower than normal noticeable by a significant decrease in GSH content, GPx, SOD, and CAT activities associated with a significantly high MDA content. Both treatments have significantly elevated SOD and CAT activities with a concomitant decrease of MDA level compared to DMBA group. However, BTG + ZnO-NPs accentuated the decrease of GSH regarding DMBA group. The results showed also that both treatments significantly activate caspase-3 enzyme and apoptosis in mammary glands. Their administration to tumor-bearing rats was found to significantly reduce plasma iron and iron-binding capacity (TIBC) compared to DMBA group. Regarding liver function, both treatments significantly reduced the increase of ALT and AST activities compared to DMBA group. However, BTG + ZnO-NPs decreased albumin below normal level. Histopathological studies showed that normalization of tissue structures was higher in BTG than BTG + ZnO-NPs treatment. According to the results obtained, it is observed that the antitumor effect of BTG alone was as strong as BTG + ZnO-NPs and even more efficient in some aspects accordingly, a combination is not needed. Thus, the novel synthetic gallium derivatives may potentially present a new hope for the development of breast cancer therapeutics, which should attract further scientific and pharmaceutical interest.

Keywords

Breast cancer Gallium trichloride Betaine ZnO-nanoparticles 

Notes

Acknowledgments

We are very grateful to Prof. Dr. Philippe Collery, Service de Cance’rologie, Polyclinique Maymard, France, for kindly providing suggestion idea of the compound together with, Prof. Dr. Abdelfattah Badawi to prepare. We also thank Prof. Dr. Helen Saada, National Center for Radiation, Research, and Technology, Atomic Energy Authority, Cairo, Egypt, and Prof. Dr. Nadia Morcos, Ain Shams University, Faculty of Science, Department of Biochemistry, Cairo, Egypt, for reviewing this article and providing many helpful suggestions.

References

  1. 1.
    Sariego J. Breast cancer in the young patient. Am Surg. 2010;76(12):1397–401.PubMedGoogle Scholar
  2. 2.
    White J, Kearins O, Dodwell D, Horgan K, Hanby AM, Speirs V. Male breast carcinoma: increased awareness needed. Breast Cancer Res. 2011;13(5):219.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 2012;36(3):237–48.PubMedCrossRefGoogle Scholar
  4. 4.
    Miyata M, Furukawa M, Takahashi K, Gonzalez FJ, Yamazoe Y. Mechanism of 7,12-dimethyl benz[a] anthracene-induced immunotoxicity: role of metabolic activation at the target organ. Jpn J Pharmacol. 2001;86(3):302–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Tabaczar S, Koceva-Chyla A, Czepas J, Pieniazek A, Piasecka-Zelga J, Gwozdzinski K. Nitroxide pirolin reduces oxidative stress generated by doxorubicin and docetaxel in blood plasma of rats bearing mammary tumor. J Physiol Pharmacol. 2012;63(2):153–63.PubMedGoogle Scholar
  6. 6.
    Aljarrah K, Mhaidat NM, Al-Akhras MAH, Aldaher AN, Albiss BA, Khaled Aledealat K, et al. Magnetic nanoparticles sensitize MCF-7 breast cancer cells to doxorubicin-induced apoptosis. World J Surg Oncol. 2012;10:62–6.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Collery P, Mohsen A, Kermagoret A, D’Angelo J, Morgant G, Desmaele D, et al. Combination of three metals for the treatment of cancer: gallium, rhenium and platinum. 1. Determination of the optimal schedule of treatment. Anticancer Res. 2012;32:2769–82.PubMedGoogle Scholar
  8. 8.
    Chitambar CR, Zivkovic-Gilgenbach Z. Role of the acidic receptosome in the uptake and retention of 67Ga by human leukemic HL60 cells. Cancer Res. 1990;50:1484–7.PubMedGoogle Scholar
  9. 9.
    Chitambar CR. Medical applications and toxicities of gallium compounds. Int J Environ Res Public Health. 2010;7:2337–61.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Friesen RW, Novak EM, Hasman D, Innis SM. Relationship of dimethylglycine, choline, and betaine with oxoproline in plasma of pregnant women and their newborn infants. J Nutr. 2007;137(12):2641–6.PubMedGoogle Scholar
  11. 11.
    Xu X, Gammon MD, Zeisel SH, Bradshaw PT, Wetmur JG, Teitelbaum SL, et al. High intakes of choline and betaine reduce breast cancer mortality in a population-based study. FASEB J. 2009;23(11):4022–8.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Parhi P, Mohanty C, Sahoo SK. Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov Today. 2012;17:1044–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Taccola L, Raffa V, Riggio C, Vittorio O, Iorio MC, Vanacore R, et al. Zinc oxide nanoparticles as selective killers of proliferating cells. Int J Nanomedicine. 2011;6:1129–40.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Altomare A, Carrozinni B, Cascarano G, Giacovazzo C, Guagliardi A, Burla MC, et al. SIRPOW. 92-a program for automatic solution of crystal structures by direct methods optimized for powder data. J Appl Crystallogr. 1994;27(3):435–6.Google Scholar
  15. 15.
    Macka S, Gilmore CJ, Edwards, C, Stewart N., Shankland, K. maXus Computer Program for the Solution and Refinement of Crystal Structures. Bruker Nonius, The Netherlands, MacScience, Japan & The University of Glasgow 1999.Google Scholar
  16. 16.
    Otwinowski, Z., Minor, W.: Methods in enzymology.In: CW, Carter, Jr. & RM, Sweet, editors New York. Academic Press; 1997;276: p. 307–326Google Scholar
  17. 17.
    Vichai V, kirtikara K. Sulphorhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;3:1112–6.CrossRefGoogle Scholar
  18. 18.
    Hodgson E. A textbook of modern toxicology. 4th ed. Hoboken: John Wiley & Sons, Inc; 2010. p. 672.Google Scholar
  19. 19.
    Barros ACSD, Muranaka ENK, Mori LJ, Pelizon CHT, Iriya K, Giocondo G, et al. Induction of experimental mammary carcinogenesis in rats with 7,12-dimethylbenz(a) anthracene. Rev Hosp Clin Fac Med Sao Paulo. 2004;59(5):257–61.PubMedGoogle Scholar
  20. 20.
    Yoshioka T, Kawada K, Shimada T, Mori M. Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol. 1970;135(3):372–6.CrossRefGoogle Scholar
  21. 21.
    Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47(2):389–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med. 1963;61:882–8.PubMedGoogle Scholar
  23. 23.
    Minami M, Yoshikawa H. A simplified assay method of superoxide dismutase activity for clinical use. Clin Chem Acta. 1979;92:337–42.CrossRefGoogle Scholar
  24. 24.
    Gross RT, Bracci R, Rudolph N, Schroeder E, Kochen JA. Hydrogen peroxide toxicity and detoxification in the erytherocytes of newborn infants. Blood. 1967;29(4):481–93.PubMedGoogle Scholar
  25. 25.
    Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 1957;28(1):56–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Gornal AC, Bardawill CJ, David MM. Determination of serum proteins by means of the biuret. J Biol Chem. 1949;177:751.Google Scholar
  27. 27.
    Doumas BT, Watson WA, Biggs HG. Albumin standards and the measurement of serum albumin with bromcresol green. Clin Chem Acta. 1971;31(1):87–96.CrossRefGoogle Scholar
  28. 28.
    Henry RJ. Clinical Chemistry, Principle and Techniques. 2nd ed. New York: Harper and Row; 1974. p. 525.Google Scholar
  29. 29.
    Patton CJ, Crouch SR. Spectrophotmetric and kinetics investigations of the Berthelot reaction for the determination of ammonia. Anal Chem. 1977;49:464–9.CrossRefGoogle Scholar
  30. 30.
    Tonner E, Barber MC, Allan GJ, Beattie J, Webster J, Bruce C, et al. Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. IGFBP-5 Mamm Dev. 2002;129:4547–57.Google Scholar
  31. 31.
    Fairbanks VF, Klee GG. Biochemical aspects of hematology. In: Teitz NW, editor. Fundamentals of clinical chemistry. 3rd ed. Philadelphia: WB saunders; 1987. p. 789–824.Google Scholar
  32. 32.
    Williams HL, Johonson DJ, Haut MJ. Simultaneous spectrophotometry of and in serum denatured with guanidine hydrochloride. Clin Chem. 1977;23:237–40.PubMedGoogle Scholar
  33. 33.
    Ribble D, Goldstein NB, Norris DA, Shellman YG. A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol. 2005;10:5–12.Google Scholar
  34. 34.
    Renvoizé C, Biola A, Pallardy M, Bréard J. Apoptosis: identification of dying cells. Cell Biol Toxicol. 1988;14(2):111–20.CrossRefGoogle Scholar
  35. 35.
    Banchroft JD, Stevens A, Turner DR. Theory and practice of histological techniques. 4th ed. New York: Churchil Livingstone; 1996.Google Scholar
  36. 36.
    Daniel WW, 5th. Biostatistics: a foundation for analysis in the health sciences, vol. 5. 5th ed. New York: John Wiley Publishers; 1991. p. 191–233.Google Scholar
  37. 37.
    Bailey TC. A review of statistical spatial analysis in geographical information systems. In: Fotheringham S, Rogerson P, editors. Spatial analysis and GIS. London: CRC Press, 2013, Ltd.; Taylor and Francis; 1994. p. 13–44.Google Scholar
  38. 38.
    Chitambar CR, Purpi DP, Woodliff J, Yang M, Wereley JP. Development of gallium compounds for treatment of lymphoma: gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circumvents lymphoma cell resistance to gallium nitrate. J Pharmacol ExpTher. 2007;322:1228–36.CrossRefGoogle Scholar
  39. 39.
    Wang F, Jiang X, Yang DC, Elliott RL, Head JF. Doxorubicin-gallium-transferrin conjugate overcomes multidrug resistance: evidence for drug accumulation in the nucleus of drug resistant MCF-7/ADR cells. Anticancer Res. 2000;20(2A):799–808.PubMedGoogle Scholar
  40. 40.
    Berggren MM, Burns LA, Abraham RT, Powis G. Inhibition of protein tyrosine phosphatases by the antitumor agent gallium nitrate. Cancer Res. 1993;53(8):1862–6.PubMedGoogle Scholar
  41. 41.
    Chua MS, Bernstein LR, Li R, So SK. Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma. Anticancer Res. 2006;26(3A):1739–44.PubMedGoogle Scholar
  42. 42.
    Reddy NS, Nirmala P, Chidambaram N, Kumar PA. Quercetin in dimethyl benzanthracene induced breast cancer in rats. Am J Pharmacol Toxicol. 2012;7(2):68–72.CrossRefGoogle Scholar
  43. 43.
    Soujanya J, Silambujanaki P, Krishna VL. Anticancer efficacy of holoptelea integrifolia, planch. against 7,12-dimethylbenz(a) anthracene induced breast carcinoma in experimental rats. Int J Pharm Pharm Sci. 2011;3:103–6.Google Scholar
  44. 44.
    Cao Y, Wang J, Henry-Tillman R, Klimberg VS. Effect of 7, 12-dimethylbenz[a]anthracene (DMBA) on gut glutathione metabolism. J Surg Res. 2001;100(1):135–40.PubMedCrossRefGoogle Scholar
  45. 45.
    Muqbil I, Banu N. Enhancement of pro-oxidant effect of 7,12-dimethylbenz(a)anthracene (DMBA) in rats by preexposure to restraint stress. Cancer Lett. 2006;240(2):213–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Kim SK, Seo JM, Chae YR, Jung YS, Park JH, Kim YC. Alleviation of dimethylnitrosamine-induced liver injury and fibrosis by betaine supplementation in rats. Chem Biol Interact. 2009;177(3):204–11. 52.PubMedCrossRefGoogle Scholar
  47. 47.
    Yang M, Chitambar CR. Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008;45:763–72.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Joseph TP, Janine PW, Chitambar CR. Gallium nitrate as a novel agent for the treatment of mantle cell lymphoma: target and mechanisms of action. Proc Am Assoc Cancer Res. 2005;46:1383–4.Google Scholar
  49. 49.
    Chitambar CR. Gallium-containing anticancer compounds. Future Med Chem. 2012;4(10):1257–72.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL. Disulfiram modulated ROS-MAPK and NFkB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer. 2011;104:1564–74.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Deshmukh Pratibha R, Shete Anjali N, GarKal KD. Comparative study of oxidative stress in carcinoma breast patients and controls. Int J Recent Trends Sci Technol. 2014;10(2):363–4.Google Scholar
  52. 52.
    Leperre A, Millart H, Prévost A, Kantelip JP, Lamiable D, Collery P. Gallium chloride effects on neonatal rat heart cells in culture, in standard and oxidative conditions. Fundam Clin Pharmacol. 1994;8:563–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Sha S, Jin H, Li X, Yang J, Ai R, Lu J. Comparison of caspase-3 activation in tumor cells upon treatment of chemotherapeutic drugs using capillary electrophoresis. Protein Cell. 2012;3(5):392–9.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Chitambar CR, Wereley JP, Matsuyama S. Gallium-induced cell death in lymphoma: role of transferrin receptor cycling, involvement of Bax and the mitochondria, and effects of proteasome inhibition. Mol Cancer Ther. 2006;5(11):2834–43.PubMedCrossRefGoogle Scholar
  55. 55.
    Elliott RL, Elliott MC, Wang F, Head JF. Breast carcinoma and the role of iron metabolism. A cytochemical, tissue culture, and ultrastructural study. Ann NY Acad Sci. 1993;698:159–66.PubMedCrossRefGoogle Scholar
  56. 56.
    Huang X. Iron overload and its association with cancer risk in humans: evidence for iron as a carcinogenic metal. Mutat Res. 2003;533(1– 2):153–71.PubMedCrossRefGoogle Scholar
  57. 57.
    Skrajnowska D, Bobrowska B, Tokarz A, Kuras M, Rybicki P, Wachowicz M. The effect of zinc- and copper sulphate supplementation on tumor and hair concentrations of trace elements (Zn, Cu, Fe, Ca, Mg, P) in rats with DMBA-induced breast cancer. Pol J Environ Stud. 2011;20(6):1585–92.Google Scholar
  58. 58.
    Skrajnowska D, Bobrowska B, Tokarz A, Kuras M. The effect of copper and resveratrol on hair mineral concentrations in rats with DMBA-induced mammary cancer. Bromatol Chem Toksykol. 2012;3:580–5.Google Scholar
  59. 59.
    Gurzau ES, Neagu C, Gurzau AE. Essential metals-case study on iron. Ecotoxicol Environ Saf. 2003;56(1):190–200.PubMedCrossRefGoogle Scholar
  60. 60.
    Bae YJ, Yeon JY, Sung CJ, Kim HS, Sung MK. Dietary intake and serum levels of iron in relation to oxidative stress in breast cancer patients. J Clin Biochem Nutr. 2009;45(3):355–60.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bobrowska-Korczak B, Skrajnowska D, Tokarz A. The effect of dietary zinc and polyphenols intake on DMBA-induced mammary tumorigenesis in rats. J Biomed Sci. 2012;19(1):43–51.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Movahedian A., Moshtaghi AA. Changes in parameters related to serum iron metabolism in gallium treated rats. J Res Med Sci. 2000;5(4).Google Scholar
  63. 63.
    Chitambar CR, Matthaeus WG, Antholine WE, Graff K, O’Brien WJ. Inhibition of leukemic HL60 cell growth by transferrin-gallium: effects on ribonucleotide reductase and demonstration of drug synergy with hydroxyurea. Blood. 1988;72:1930–6.PubMedGoogle Scholar
  64. 64.
    Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med. 1988;310:1047–52.CrossRefGoogle Scholar
  65. 65.
    Warrell RP. Jr., Bockman RS. Important Advances in Oncology. In: DeVita VT., Hellman S., Rosenberg SA.,editors; Philadelphia: J.B. Lippincott:1989 pp. 205–220.Google Scholar
  66. 66.
    Lee A, Levine M. Treatment of venous thromboemobolism in cancer patients. Cancer Control. 2005;12:17–21.PubMedGoogle Scholar
  67. 67.
    Bedi PS, Priyanka S. Effects of garlic against 7,12- dimethyl benzanthracene induced toxicity in Wistar albino rats. Asian J Pharm Clin Res. 2012;5(4):170–3.Google Scholar
  68. 68.
    Said UZ, Ahmed NH, Medhat AM, Mustafa MM. Effects of omega-3 fatty acids against Ehrlich carcinoma-induced hepatic dysfunction. J Cancer Res Exp Oncol. 2014;6(2):20–8.CrossRefGoogle Scholar
  69. 69.
    Krecic-Shepard ME, Shepard DR, Mullet D, Apseloff G, Weisbrode SE, Gerber N. Gallium nitrate suppresses the production of nitric oxide and liver damage in a murine model of LPS-induced septic shock. Life Sci. 1999;65(13):1359–71.PubMedCrossRefGoogle Scholar
  70. 70.
    Ho M, Wu KY, Chein HM, Chen LC, Cheng TJ. Pulmonary toxicity of inhaled nanoscale and fine zinc oxide-particles: mass and surface area as an exposure metric. Inhal Toxicol. 2011;23:947–56.PubMedCrossRefGoogle Scholar
  71. 71.
    Fulda S. Tumor resistance to apoptosis. Int J Cancer. 2009;124(3):511–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30(1):87–100.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Greene BT, Thorburn J, Willingham MC, Thorburn A, Planalp RP, Brechbiel MW, et al. Activation of caspase pathways during iron chelator-mediated apoptosis. J Biol Chem. 2002;277(28):25568–75.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Ahmed Salem
    • 1
  • Eman Noaman
    • 2
  • Eman kandil
    • 1
  • Abdelfattah Badawi
    • 3
  • Nihal Mostafa
    • 1
  1. 1.Department of Biochemistry, Faculty of ScienceAin Shams UniversityCairoEgypt
  2. 2.Medical Laboratory Department, Faculty of Applied Medical ScienceAl Majmaah University, KSA and National Center for Radiation Research and Technology. Atomic Energy AuthorityCairoEgypt
  3. 3.Petrochemical DepartmentEgyptian Petroleum Research InstituteCairoEgypt

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