Nacházíte se zde: Úvod > Journal of Applied Biomedicine > 11_2 > arantes11_2.htm

arantes11_2.htm

ISSN 1214-0287 (on-line), ISSN 1214-021X (printed)
J Appl Biomed
Volume 11 (2013), No 2, p 79-92
DOI 10.2478/v10136-012-0034-7

Meloxicam synergistically enhances the in vitro effects of sunitinib malate on bladder-cancer cells

Regina Arantes-Rodrigues, Rosario Pinto-Leite, Lio Fidalgo-Goncalves, Isabel Gaivao, Aura Colaco, Paula Oliveira, Lucio Santos

Address: Paula Oliveira, Department of Veterinary Sciences, CECAV, University of Tras-os-Montes and Alto Douro, Vila Real 5001-801, Portugal
pamo@utad.pt

Received 31st December 2012.
Revised 2nd January 2013.
Published online 8th January 2013.

Full text article (pdf)
Full text article (html)

SUMMARY
To evaluate the in vitro effects of sunitinib malate and meloxicam in isolation, and to analyse the ability of meloxicam to enhance the cytotoxicity of sunitinib malate in three human bladder-cancer cell lines. Cell lines were treated with sunitinib malate and meloxicam, either in isolation or combined. Leishman staining, MTT method, comet assay, MDC staining and M30 CytoDEATH antibody were performed. The Chou and Talalay method was applied. Sunitinib malate and meloxicam supressed cell proliferation in bladder-cancer cells in isolation, in a concentration-dependent manner. Treatment of bladder-cancer cells with a combination of sunitinib malate and meloxicam showed a synergistic effect. When exploring the mechanism of this combination by means of comet assay, there is the suggestion that meloxicam increases sunitinib malate cytotoxicity through DNA damage. Autophagic and apoptotic studies show a greater incidence of autophagic vacuoles and early apoptotic cells when the combined treatment was put into use. In isolation, sunitinib malate and meloxicam demonstrated anti-tumour effects in our study. Furthermore, simultaneous exposure of cells to sunitinib malate and meloxicam provided a combinatorial beneficial effect. This hints at the possibility of a new combined therapeutic regimen, which could lead to improvements in the treatment of patients with bladder cancer.

KEY WORDS
bladder cancer; bladder-cancer cell lines; sunitinib malate; meloxicam; synergistic

REFERENCES
Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2: 471-478, 2003.
[PubMed]

Awara WM, El-Sisi AE, El-Sayad ME, Goda AE. The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin? Pharmacol Res. 50: 487-498, 2004.
[CrossRef] [PubMed]

Bellmunt J, Gonzalez-Larriba JL, Prior C, Maroto P, Carles J, Castellano D, Mellado B, Gallardo E, Perez-Gracia JL, Aguilar G, Villanueva X, Albanell J, Calvo A. Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity. Ann Oncol. 22: 2646-2653, 2011.
[CrossRef] [PubMed]

Berger J. The age of biomedicine: current trends in traditional subjects. J Appl Biomed. 9: 57-61, 2011.
[CrossRef] [JAB]

Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA. 99: 13926-13931, 2002.
[CrossRef] [PubMed]

Chen L, He Y, Huang H, Liao H, Wei W. Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study. Med Oncol. 25: 161-171, 2008.
[CrossRef] [PubMed]

Chou TC, Talalay P. Quantitative analysis of concentration-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22: 27-55, 1984.
[CrossRef]

Collins AR. The Comet Assay for DNA Damage and Repair: Principles, Applications, and Limitations. Mol Biotechnol. 26: 249-461, 2004.
[CrossRef]

Collins AR, Oscoz AA, Brunborg G, Gaivao I, Giovannelli L, Kruszewski M, Smith CC, Stetina R. The comet assay: topical issues. Mutagenesis. 23: 143-151, 2008.
[CrossRef] [PubMed]

Compare D, Nardone O, Nardone G. Non-Steroidal Anti-Inflammatory Drugs in the Carcinogenesis of the Gastrointestinal Tract. Pharmaceuticals. 3: 2495-2516, 2010.
[CrossRef]

Cuervo AM. Autophagy: in sickness and in health. Trends Cell Biol. 14: 70-77, 2004.
[CrossRef] [PubMed]

Cuneo KC, Geng L, Fu A, Orton D, Hallahan DE, Chakravarthy AB. SU11248 (sunitinib) sensitizes pancreatic cancer to the cytotoxic effects of ionizing radiation. Int J Radiat Oncol Biol Phys. 71: 873-879, 2008.
[CrossRef] [PubMed]

Dhawan D, Jeffreys AB, Zheng R, Stewart JC, Knapp DW. Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells. Mol Cancer Ther. 7: 897-904, 2008.
[CrossRef] [PubMed]

Drell TL 4th, Zanker KS, Entschladen F. Translational research in oncology: The need of additional in vitro preclinical testing methods for new drugs. Curr Pharm Des. 18: 3416-3420, 2012.
[CrossRef] [PubMed]

Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 107: 1183-1188, 1994.
[PubMed]

Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73: 1907-1916, 2005.
[CrossRef] [PubMed]

Furst DE. Meloxicam: Selective COX-2 inhibition in clinical practice. Semin Arthritis Rheum. 26: 21-27, 1997.
[CrossRef] Gallagher DJ, Milowsky MI, Gerst SR, Ishill N, Riches J, Regazzi A, Boyle MG, Trout A, Flaherty AM, Bajorin DF. Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol. 28: 1373-1379, 2010.
[CrossRef] [PubMed]

Goldman AP, Williams CS, Sheng H, Lamps LW, Williams VP, Pairet M, Marrow JD, DuBois RN. Meloxicam inhibits the growth of colorectal cancer cell. Carcinogenesis. 19: 2195-2199, 1998.
[CrossRef] [PubMed]

Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H. Overexpression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate. 42: 73-78, 2000.
[CrossRef]

Hamama AK, Ray J, Day RO, Brien JE. Simultaneous Determination of Rofecoxib and Celecoxib in Human Plasma by High-Performance Liquid Chromatography. J Chromatogr Sci. 43: 351-354, 2005.
[PubMed]

Hida T, Kozaki K, Muramatsu H, Masuda A, Shimizu S, Mitsudomi T, Sugiura T, Ogawa M, Takahashi T. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res. 6: 2006-2011, 2000.
[PubMed]

Huang S, Sinicrope FA. Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy. 6: 256-269, 2010.
[CrossRef] [PubMed]

Hwang D, Scollard D, Byrne J, Levine E. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst. 90: 455-460, 1998.
[CrossRef] [PubMed]

Jacobs BL, Montgomery JS, Zhang Y, Skolarus TA, Weizer AZ, Hollenbeck BK. Disparities in bladder cancer. Urol Oncol. 30: 81-88, 2012.
[CrossRef] [PubMed]

Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 441: 431-436, 2006.
[CrossRef] [PubMed]

Kern MA, Schoneweiss MM, Sahi D, Bahlo M, Haugg AM, Kasper HU, Dienes HP, Kaferstein H, Breuhahn K, Schirmacher P. Cyclooxygenase-2 inhibitors suppress the growth of human hepatocellular carcinoma implants in nude mice. Carcinogenesis. 25: 1193-1199, 2004.
[CrossRef] [PubMed]

Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nature Rev Cancer. 5: 726-734, 2005.
[CrossRef] [PubMed]

Kooijman M, van Meer PJ, Moors EH, Schellekens H. Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance? Expert Opin Drug Saf. 11: 797-801, 2012.
[CrossRef] [PubMed]

Mager DE, Woo S, Jusko WJ. Scaling pharmacodynamics from in vitro and preclinical animal studies to humans. Drug Metab Pharmacokinet. 24: 16-24, 2009.
[CrossRef] [PubMed]

Michaud DS. Chronic inflammation and bladder cancer. Urol Oncol. 25: 260-268, 2007.
[CrossRef] [PubMed]

Mizutani Y, Nakanishi H, Li YN, Sato N, Kawauchi A, Miki T. Enhanced sensitivity of bladder cancer cells to cisplatin mediated cytotoxicity and apoptosis in vitro and in vivo by the selective cyclooxygenase-2 inhibitor JTE-522. J Urol. 172: 1474-1479, 2004.
[CrossRef] [PubMed]

Montejo C, Barcia E, Negro S, Fernandez-Carballido A. Effective antiproliferative effect of meloxicam on prostate cancer cells: Development of a new controlled release system. Int J Pharm. 387: 223-229, 2010.
[CrossRef] [PubMed]

Morimoto AM, Tan N, West K, McArthur G, Toner GC, Manning WC, Smolich BD, Cherrington JM. Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor. Oncogene. 23: 1618-1626, 2003.
[CrossRef] [PubMed]

Munafo DB, Colombo MI. A novel assay to study autophagy: regulation of autophagosome vacuole size by amino acid deprivation. J Cell Sci. 114: 3619-3629, 2001.
[PubMed]

Naruse T, Nishida Y, Ishiguro N. Synergistic effects of meloxicam and conventional cytotoxic drugs in human MG-63 osteosarcoma cells. Biomed Pharmacother. 61: 338-346, 2007.
[CrossRef] [PubMed]

Pan F, Tian J, Zhang X, Zhang Y, Pan Y. Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. J Cancer Res Clin Oncol. 137: 1397-1408, 2011.
[CrossRef] [PubMed]

Ping SY, Wu CL, Yu DS. Sunitinib can enhance BCG mediated cytotoxicity to transitional cell carcinoma through apoptosis pathway. Urol Oncol. 30: 652-659, 2012.
[CrossRef] [PubMed]

Scheiman JM, Hindley CE. Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther. 32: 667-677, 2010.
[CrossRef] [PubMed]

Sonpavde G, Jian W, Liu H, Wu MF, Shen SS, Lerner SP. Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model. Urol Oncol. 27: 391-399, 2009.
[CrossRef] [PubMed]

Tsubouchi Y, Mukai S, Kawahito Y, Yamada R, Kohno M, Inoue K, Sano H. Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis. 19: 2195-2199, 2000.

Tsuchida A, Itoi T, Kasuya K, Endo M, Katsumata K, Auki T, Suzuki M, Aoki K. Inhibitory effect of meloxicam, a cyclooxigenase-2 inhibitor, on N-nitrosobis (2-oxopropyl) amine induced biliary carcinogenesis in Syrian hamsters. Carcinogenesis. 26: 1922-1928, 2005.
[CrossRef] [PubMed]

Verbeek HH, Alves MM, de Groot JW, Osinga J, Plukker JT, Links TP, Hofstra RM. The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. J Clin Endocrinol Metab. 96: 991-995, 2011.
[CrossRef] [PubMed]

Watkins DN, Lenzo JC, Segal A, Garlepp MJ, Thompson PJ. Expression and localization of cyclo-oxygenase isoforms in non-small cell lung cancer. Eur Respir J. 14: 412-418, 1999.
[CrossRef] [PubMed]

Wiedenmann B, Pavel M, Kos-Kudla B. From targets to treatments: a review of molecular targets in pancreatic neuroendocrine tumors. Neuroendocrinology. 94: 177-190, 2011.
[CrossRef] [PubMed]

Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 18: 7908-7916, 1999.
[CrossRef] [PubMed]

Wolfesberger B, Hoelzl C, Walter I, Reider GA, Fertl G, Thalhammer JG, Skalicky M, Egerbacher M. In vitro effects of meloxicam with or without doxorubicin on canine osteosarcoma cells. J Vet Pharmacol Ther. 29: 15-23, 2006.
[CrossRef] [PubMed]

Yoon CY, Lee JS, Kim BS, Jeong SJ, Hong SK, Byun SS, Lee SE. Sunitinib malate synergistically potentiates anti-tumor effect of gemcitabine in human bladder cancer cells. Korean J Urol. 52: 55-63, 2011.
[CrossRef] [PubMed]

Zhao Y, Xue T, Yang X, Zhu H, Ding X, Lou L, Lu W, Yang B, He Q. Autophagy plays an important role in sunitinib-mediated cell death in H9c2 cardiac muscle cells. Toxicol Appl Pharmacol. 248: 20-27, 2010.
[CrossRef] [PubMed]
CITED

Arantes-Rodrigues R, Colaco A, Pinto-Leite R, Oliveira PA. In Vitro and In Vivo Experimental Models as Tools to Investigate the Efficacy of Antineoplastic Drugs on Urinary Bladder Cancer. Anticancer Res. 33: 1273-1296, 2013.

BACK