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  • 1 Faculty of Veterinary Medicine, Istanbul University, Istanbul, Turkey
  • 2 Aziz Sancar Experimental Medicine Research Institute, Istanbul University, Istanbul, Turkey
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Currently, there is a growing interest in combining anticancer drugs with the aim to improve outcome in patients suffering from tumours and reduce the long-term toxicity associated with the current standard of treatment. In this study, we evaluated the possible role of deracoxib against the toxicity of doxorubicin on normal canine mammary epithelial cells. The effect of deracoxib and doxorubicin combination on cell viability was determined by MTT assay. Apoptosis was characterised by flow cytometry. Cell nitrite concentrations were measured with the Griess reaction. Deracoxib (50 and 100 μM) treatment decreased the cytotoxic action of doxorubicin at 0.9 μM in the cells, from 33.63% to 13.4% and 25.82%, respectively. Our results also showed that the reverse effect of deracoxib on doxorubicin-induced cytotoxic activity in the cells was associated with a marked (3.04- to 3.57-fold) decrease in apoptosis. In additional studies identifying the mechanism of the observed effect, deracoxib exhibited an activity to prevent doxorubicin-mediated overproduction of nitric oxide in the cells. Our in vitro study results indicate that deracoxib (50 and 100 μM) can be beneficial in protecting normal cells from the toxic effect of doxorubicin in conjunction with apoptosis by the modulation of nitric oxide production.

  • Abou El Hassan, M. A. I., Verheul, H. M. W., Jorna, A. S., Schalkwijk, C., van Bezu, J., van der Vijgh, W. J. F. and Bast, A. (2003): The new cardioprotector monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro. Br. J. Cancer. 89, 357362.

    • Search Google Scholar
    • Export Citation
  • Akdeniz, N., Esrefoglu, M., Keles, M., Karakuzu, A. and Atasoy, M. (2004): Serum interleukin-2, interleukin- 6, tumour necrosis factor-alpha and nitric oxide levels in patients with Behcet’s disease. Ann. Acad. Med. Singap. 33, 596599.

    • Search Google Scholar
    • Export Citation
  • Al-Lazikani, B., Banerji, U. and Workman, P. (2012): Combinational drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30, 679692.

    • Search Google Scholar
    • Export Citation
  • Alshafie, G. A., Abou-Issa, H. M., Seibert, K. and Harris, R. E. (2000): Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. Oncol. Rep. 7, 13771381.

    • Search Google Scholar
    • Export Citation
  • Asanuma, M., Nishibayashi-Asanuma, S., Miyazaki, I., Kohno, M. and Ogawa, N. (2001): Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals. J. Neurochem. 76, 18951904.

    • Search Google Scholar
    • Export Citation
  • Awara, W. M., El-Sisi, A. E., El-Sayad, M. E. and Goda, A. E. (2004): The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumor activity of doxorubicin? Pharmacol. Res. 50, 487498.

    • Search Google Scholar
    • Export Citation
  • Bakirel, T., Ustun Alkan, F., Ustuner, O., Cinar, S., Yildirim, F., Erten, G. and Bakirel, U. (2016): Synergistic growth inhibitory effect of deracoxib with doxorubicin against a canine mammary tumor cell line, CMT-U27. J. Vet. Med. Sci. 78, 657668.

    • Search Google Scholar
    • Export Citation
  • Chen, L. G., Yang, L. L. and Wang, C. C. (2008): Anti-inflammatory activity of mangostins from Garcinia mangostana. Food Chem. Toxicol. 46, 688693.

    • Search Google Scholar
    • Export Citation
  • Du, Z. Y. and Li, X. Y. (1999): Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro. Int. J. Immunopharmacol. 21, 219225.

    • Search Google Scholar
    • Export Citation
  • Elmore, S. (2007): Apoptosis: A review of programmed cell death. Toxicol. Pathol. 35, 495516.

  • Falandry, C., Canney, P. A., Freyer, G. and Dirix, L. Y. (2009): Role of combination therapy with aromatase and cyclooxygenase-2 inhibitors in patients with metastatic breast cancer. Ann. Oncol. 20, 615620.

    • Search Google Scholar
    • Export Citation
  • Farivar, R. S., Chobanian, A. V. and Brecher, P. (1996): Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ. Res. 78, 759768.

    • Search Google Scholar
    • Export Citation
  • Gallouet, A. S., Travert, M., Bresson-Bepoldin, L., Guilloton, F., Pangault, C., Caulet-Maugendre, S., Lamy, T., Tarte, K. and Guillaudeux, T. (2014): COX-2-independent effects of celecoxib sensitize lymphoma B cells to TRAIL-mediated apoptosis. Clin. Cancer Res. 20, 26632673.

    • Search Google Scholar
    • Export Citation
  • Gustafson, D. L. and Page, R. L. (2013): Cancer chemotherapy. In: Withrow, S., Vail, D. and Page, R. (eds) Withrow and MacEwen’s Small Animal Clinical Oncology. 5th edition, Elsevier Health Sciences, Missouri. pp. 157179.

    • Search Google Scholar
    • Export Citation
  • Hao, E., Mukhopadhyay, P., Cao, Z., Erdélyi, K., Holovac, E., Liaudet, L., Lee, W-S., Haskó, G., Mechoulam, R. and Pacher, P. (2015): Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis. Mol. Med. 21, 3845.

    • Search Google Scholar
    • Export Citation
  • Hilovska, L., Jendzelovsky, R. and Fedorocko, P. (2015): Potency of non-steroidal anti-inflammatory drugs in chemotherapy (Review). Mol. Clin. Oncol. 3, 312.

    • Search Google Scholar
    • Export Citation
  • Indran, I. R., Tufo, G., Pervaiz, S. and Brenner, C. (2011): Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim. Biophys. Acta 1807, 735745.

    • Search Google Scholar
    • Export Citation
  • Ismael, G. F. V., Rosa, D. D., Mano, M. S. and Awada, A. (2008): Novel cytotoxic drugs: Old challenges, new solutions. Cancer Treat. Rev. 34, 8191.

    • Search Google Scholar
    • Export Citation
  • Jastrzebska, E., Flis, S., Rakowska, A., Chudy, M., Jastrzebski, Z., Dybko, A. and Brzozka, Z. (2013): A microfluidic system to study the cytotoxic effect of drugs: The combined effect of celecoxib and 5-fluorouracil on normal and cancer cells. Microchim. Acta 180, 895901.

    • Search Google Scholar
    • Export Citation
  • Karayannopoulou, M., Kaldrymidou, E., Constantinidis, T. C. and Dessiris, A. (2001): Adjuvant postoperative chemotherapy in bitches with mammary cancer. J. Vet. Med. A 48, 8596.

    • Search Google Scholar
    • Export Citation
  • Karayannopoulou, M., Kaldrymidou, E., Constantinidis, T. C. and Dessiris, A. (2005): Histological grading and prognosis in dogs with mammary carcinomas: Application of a human grading method. J. Comp. Pathol. 133, 246252.

    • Search Google Scholar
    • Export Citation
  • Koki, A. T. and Masferrer, J. L. (2002): Celecoxib: A specific COX-2 inhibitor with anticancer properties. Cancer Control 9, 2835.

  • Kunwar, A., Barik, A., Mishra, B., Rathinasamy, K., Pandey, R. and Priyadarsini, K. I. (2008): Quantitative cellular uptake, localization and cytotoxicity of curcumin in normal and tumor cells. Biochim. Biophys. Acta 1780, 673679.

    • Search Google Scholar
    • Export Citation
  • Leth-Larsen, R., Lund, R. R. and Ditzel, H. J. (2010): Plasma membrane proteomics and its application in clinical cancer biomarker discovery. Mol. Cell. Proteomics 9, 13691382.

    • Search Google Scholar
    • Export Citation
  • McMillan, S. K., Boria, P., Moore, G. E., Widmer, W.R., Bonney, P. L. and Knapp, D. W. (2011): Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder. JAVMA 239, 10841089.

    • Search Google Scholar
    • Export Citation
  • Meng, X., Zhang, Q., Zheng, G., Pang, R., Hua, T., Yang, S. and Li, J. (2014): Doxorubicin combined with celecoxib inhibits tumor growth of medullary thyroid carcinoma in xenografted mice. Oncol. Lett. 7, 20532058.

    • Search Google Scholar
    • Export Citation
  • Meyer, M., Schreck, R. and Baeuerle, P. A. (1993): H2O2 and antioxidants have opposite effects on activation of NF-Kb and AP-1 in intact cells: aP-1 as secondary antioxidant-responsive factor. EMBO J. 12, 20052015.

    • Search Google Scholar
    • Export Citation
  • Mizutani, H., Tada-Oikawa, S., Hiraku, Y., Kojima, M. and Kawanishi, S. (2005): Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sci. 76, 14391453.

    • Search Google Scholar
    • Export Citation
  • Mukhopadhyay, P., Rajesh, M., Batkai, S., Kashiwaya, Y., Hasko, G., Liaudet, L., Szabo, C. and Pacher, P. (2009): Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 296, 14661483.

    • Search Google Scholar
    • Export Citation
  • Narang, A. S. and Desai, D. S. (2009): Anticancer drug development. In: Lu, Y. and Mahato, R. I. (eds) Pharmaceutical Perspectives of Cancer Therapeutics, 16th edition. Springer Science & Business Media, New York. pp. 4992.

    • Search Google Scholar
    • Export Citation
  • Octavia, Y., Tocchetti, C. G., Gabrielson, K. L., Janssens, S., Crijns, H. J. and Moens, A. L. (2012): Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol. 52, 12131225.

    • Search Google Scholar
    • Export Citation
  • Ozen, S., Usta, Y., Sahin-Erdemli, I., Orhan, D., Gumusel, B., Yang, B., Gursoy, Y., Tulunay, O., Dalkara, T., Bakkaloglu, A. and El Nahas, M. (2001): Association of nitric oxide production and apoptosis in a model of experimental nephropathy. Nephrol. Dial. Transpl. 16, 3238.

    • Search Google Scholar
    • Export Citation
  • Ozgocmen, S., Ardicoglu, O., Erdogan, H., Fadillioglu, E. and Gudul, H. (2005): In vivo effect of celecoxib and tenoxicam on oxidant/anti-oxidant status of patients with knee osteoarthritis. Ann. Clin. Lab. Sci. 35, 137143.

    • Search Google Scholar
    • Export Citation
  • Pagnini, U., Florio, S., Lombardi, P., d’Angelo, D., Avallone, L., Galdiero, M., Iovane, G., Tortora, G. and Pagnini, G. (2000): Modulation of anthracycline activity in canine mammary tumour cells in vitro by medroxyprogesterone acetate. Res. Vet. Sci. 69, 255262.

    • Search Google Scholar
    • Export Citation
  • Patel, M. I., Subbaramaiah, K., Du, B., Chang, M., Yang, P., Newman, R.A., Cordon-Cardo, C., Thaler, H. T. and Dannenberg, A. J. (2005): Celecoxib inhibits prostate cancer growth: Evidence of a cyclooxygenase-2-independent mechanism. Clin. Cancer Res. 11, 19992007.

    • Search Google Scholar
    • Export Citation
  • Pereg, D. and Lishner, M. (2005): Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer. J. Intern. Med. 258, 115123.

    • Search Google Scholar
    • Export Citation
  • Pereira, P. D., Lopes, C. C., Matos, A. J. F., Pinto, D., Gartner, F., Lopes, C. and Medeiros, R. (2009): Influence of catechol-o-methyltransferase (COMT) genotypes on the prognosis of canine mammary tumors. Vet. Pathol. 46, 12701274.

    • Search Google Scholar
    • Export Citation
  • Rai, R. B., Saminathan, M., Dhama, K., Ranganath, G. J., Murugesan, V., Kannan, K., Pavulraj, S., Gopalakris, A. and Suresh, C. (2014): Histopathology and immunohistochemical expression of n-methyl-n-nitrosourea (NMU) induced mammary tumours in Sprague-Dawley rats. Asian J. Anim. Vet. Adv. 9, 621640.

    • Search Google Scholar
    • Export Citation
  • Ralph, S., Pritchard, R., Rodríguez-Enríquez, S., Moreno-Sánchez, R. and Ralph, R. (2015): Hitting the bull’s-eye in metastatic cancers — NSAIDs elevate ROS in mitochondria, inducing malignant cell death. Pharmaceuticals (Basel) 8, 62106.

    • Search Google Scholar
    • Export Citation
  • Rao, P. and Knaus, E. E. (2008): Evaluation of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J. Pharm. Pharm. Sci. 11, 81110.

    • Search Google Scholar
    • Export Citation
  • Rayburn, E. R., Ezell, S. J. and Zhang, R. (2009): Anti-inflammatory agents for cancer therapy. Mol. Cell. Pharmacol. 1, 2943.

  • Rehman, M. U., Tahir, M., Khan, A. Q., Khan, R., Oday, O. H., Lateef, A., Hassan, S.K., Rashid, S., Ali, N., Zeeshan, M. and Sultana, S. (2014): D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NF B in kidneys of Wistar rats. Exp. Biol. Med. 239, 465476.

    • Search Google Scholar
    • Export Citation
  • Roberts, E. S., Van Lare, K. A., Marable, B. R. and Salminen, W. F. (2009): Safety and tolerability of 3-week and 6-month dosing of Deramaxx® (Deracoxib) chewable tablets in dogs. J. Vet. Pharmacol. Ther. 32, 329337.

    • Search Google Scholar
    • Export Citation
  • Sanchez de Miguel, L., de Frutos, T., Gonzalez-Fernandez, F., del Pozo, V., Lahoz, C., Jimenez, A., Rico, L., Garcia, R., Aceituno, E., Millas, I., Gomez, J., Farre, J., Casado, S. and Lopez- Farre, A. (1999): Aspirin inhibits inducible nitric oxide synthase expression and tumor necrosis factor-alpha release by cultured smooth muscle cells. Eur. J. Clin. Invest. 29, 9399.

    • Search Google Scholar
    • Export Citation
  • Schreck, R., Rieber, P. and Baeuerle, P. A. (1991): Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV–1. EMBO J. 10, 22472258.

    • Search Google Scholar
    • Export Citation
  • Shi, Y. (2001): A structural view of mitochondria-mediated apoptosis. Nat. Struct. Mol. Biol. 8, 394401.

  • Simon, D., Schoenrock, D., Baumgärtner, W. and Nolte, I. (2006): Postoperative adjuvant treatment of invasive malignant mammary gland tumors in dogs with Doxorubicin and Docetaxel. J. Vet. Intern. Med. 20, 11841190.

    • Search Google Scholar
    • Export Citation
  • Smalley, M. J. (2010): Isolation, culture and analysis of mouse mammary epithelial cells. In: Ward, A. and Tosh, D. (eds) Mouse Cell Culture, 1st edition. Springer Science & Business Media, LCC. pp. 139170.

    • Search Google Scholar
    • Export Citation
  • Souza, C. H. M., Toledo-Piza, E., Amorin, R., Barboza, A. and Tobias, K. M. (2009): Inflammatory mammary carcinoma in 12 dogs: Clinical features, cyclooxygenase-2 expression, and response to piroxicam treatment. Can. Vet. J. 50, 506510.

    • Search Google Scholar
    • Export Citation
  • Todorova, I., Simeonova, G., Simeonov, R. and Dinev, D. (2005): Efficacy and toxicity of doxorubicin and cyclophosphamide chemotherapy in dogs with spontaneous mammary tumours. TJS 3, 5158.

    • Search Google Scholar
    • Export Citation
  • Ustun Alkan, F., Bakirel, T., Ustuner, O. and Yardibi, H. (2014): In vitro effects of doxorubicin and deracoxib on oxidative-stress-related parameters in canine mammary carcinoma cells. Acta Vet. Hung. 62, 372385.

    • Search Google Scholar
    • Export Citation
  • Ustun Alkan, F., Ustuner, O., Bakirel, T., Cinar, S., Erten, G. and Deniz, G. (2012): The effects of piroxicam and deracoxib on canine mammary tumour cell line. Sci. World J. 2012, 18.

    • Search Google Scholar
    • Export Citation
  • van Wijngaarden, J., Van Beek, E., Van Rossum, G., Van Der Bent, C., Hoekman, K., Van Der Pluijm, G., Van Der Pol, M.A., Broxterman, H.J., Van Hinsbergh, V. W. M. and Löwik, C. W. G. M. (2007): Celecoxib enhances doxorubicin-induced cytotoxicity in MDA-MB231 cells by NF-κB-mediated increase of intracellular doxorubicin accumulation. Eur. J. Cancer 43, 433442.

    • Search Google Scholar
    • Export Citation
  • Wolfe, L. G., Smith, B. B., Toivio-Kinnucan, M. A., Sartin, E. A., Kwapien, R.P., Henderson, R. A. and Barnes, S. (1986): Biologic properties of cell lines derived from canine mammary carcinomas. J. Natl Cancer Inst. 77, 783792.

    • Search Google Scholar
    • Export Citation
  • Wolfesberger, B., Hoelzl, C., Walter, I., Reider, G. A., Fertl, G., Thalhammer, J. G., Skalicky, M. and Egerbacher, M. (2006): In vitro effects of meloxicam with or without doxorubicin on canine osteosarcoma cells. J. Vet. Pharmacol. Ther. 29, 1523.

    • Search Google Scholar
    • Export Citation