Primeiramente, foi possível concluir que o paclitaxel é um quimioterápico capaz de induzir neuropatia periférica na dose de 5 mg/kg em camundongos Swiss. Além disso, o presente trabalho demonstrou que a NAC, ácido lipoico e vitamina E utilizados na dose de 50 mg/kg foram capazes de reduzir a nocicepção mecânica e térmica provocada pela neuropatia induzida pelo paclitaxel. Ainda, observamos que os antioxidantes combinados com paclitaxel resultou em um efeito antitumoral, embora o uso isolado do quimioterápico não foi eficaz sobre a linhagem de células utilizadas para induzir o tumor in vivo.
Com relação ao quadro de estresse oxidativo provocado pelo paclitaxel, os três antioxidantes utilizados foram capazes de reduzir da peroxidação lipídica no fígado. No coração e no rim, o paclitaxel não causou lipoperoxidação, e o efeito dos antioxidantes não foi possível de ser determinado. Não houve resultados significativos sobre a quantidade de grupamentos sulfidril totais e proteínas carboniladas em nenhum dos órgãos analisados. Ainda, o quimioterápico e os antioxidantes não foram tóxicos para os tecidos renal e hepático.
Concluindo, os resultados sustentam a hipótese de que os antioxidantes são fármacos em potencial para o tratamento da neuropatia periférica induzida por paclitaxel. Porém, estudos não-clínicos mais aprofundados e, principalmente, clínicos randomizados devem ser realizados.
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REFERÊNCIAS
ALUIGI M. G., DE FLORA S., D’AGOSTINI F., ALBINI A. AND FASSINA G. (2000). Antiapoptotic and antigenotoxic effects of N-acetylcysteine in human cells of endothelial origin. Anti- cancer Res. 20: 3183–3187.
ARETI, A., YERRA, V. G., NAIDU, V., & KUMAR, A. (2014). Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biology, 2, 289–295. ARGYRIOU, A. A., CHRONI, E., KOUTRAS, A., ICONOMOU, G.,
PAPAPETROPOULOS, S., POLYCHRONOPOULOS, P., & KALOFONOS, H. P. (2006). Preventing Paclitaxel-Induced Peripheral Neuropathy: A Phase II Trial of Vitamin E
Supplementation. Journal of Pain and Symptom Management, 32(3), 237–244. ARGYRIOU, A. A., KOLTZENBURG, M., POLYCHRONOPOULOS, P.,
PAPAPETROPOULOS, S., & KALOFONOS, H. P. (2008). Peripheral nerve damage associated with administration of taxanes in patients with cancer. Critical Reviews in Oncology/Hematology, 66(3), 218–228.
ARUOMA, O. I., B. HALLIWELL, B. M. HOEY, AND J. BUTLER. (1989). The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biol. Med. 6:593–597.
A. HORST, J.A. DE SOUZA, M.C.Q. SANTOS, A.P.K. RIFFEL, C. KOLBERG, and W.A. PARTATA. (2017). Effects of N-acetylcysteine on spinal cord oxidative stress biomarkers in rats with neuropathic pain. Braz J Med Biol Res. 50(12): e6533.
AZZI, A. (2007). Molecular mechanism of α-tocopherol action. Free Radical Biology and
Medicine, 43(1), 16–21.
BARON, R., BINDER, A., & WASNER, G. (2010). Neuropathic pain: diagnosis,
pathophysiological mechanisms, and treatment. The Lancet Neurology, 9(8), 807–819. BARTON, D. L., WATSON, J. C., & LOPRINZI, C. L. (2009). Chemotherapy-Induced Peripheral Neuropathy: Prevention and Treatment. Clinical Pharmacology & Therapeutics, 90(3), 377–387.
BILSKA, A., & WODEK, L. (2005). Lipoic acid-the drug of the future? Pharmacological Reports. 57, 570-577.
BREAST CANCER ORGANIZATION. U.S. Breast Cancer Statistics. Disponível em: <https://www.breastcancer.org/symptoms/understand_bc/statistics>. Acesso em: 27 abr. 2019. BREAST CANCER ORGANIZATION. What is breast cancer? Disponível: <https://www.breastcancer.org/symptoms/understand_bc/what_is_bc>. Acesso em: 27 abr. 2019.
CAI, T., FASSINA, G., MORINI, M., ALUIGI, M. G., MASIELLO, L., FONTANINI, G., ALBINI, A. (1999). N-acetylcysteine inhibits endothelial cell invasion and angiogenesis.
46
Laboratory Investigation; a Journal of Technical Methods and Pathology, 79(9), 1151– 1159.
CARVALHO, L.F; SILVA, A.M.F; CARVALHO, A.A. (2017) The use of antioxidant agents for chemotherapy- induced peripheral neuropathy treatment in animal models. Clinical And Experimental: Pharmacology and Physiology. Austrália, v. 44, p.971-979.
CASCINU S, CORDELLA L, DEL FERRO E, et al. (1995). Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. Journal of Clinical Oncology;13(1):26– 32.
CAVALETTI, G., FRIGENI, B., LANZANI, F., MATTAVELLI, L., SUSANI, E.,
ALBERTI, P., et al. (2010). Chemotherapy-induced peripheral neurotoxicity assessment: A critical revision of the currently available tools. European Journal of Cancer, 46(3), 479– 494..
CHAPLAN, S. R., BACH, F. W., POGREL, J. W., CHUNG, J. M., & YAKSH, T. L. (1994). Quantitative assessment of tactile allodynia in the rat paw. Journal of Neuroscience
Methods, 53(1), 55–63.
CONSTANTINOU, C., PAPAS, A., & CONSTANTINOU, A. I. (2008). Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs. International Journal of Cancer, 123(4), 739–752. https://doi.org/10.1002/ijc.23689
DAS GUPTA, S., SO, J. Y., WALL, B., WAHLER, J., SMOLAREK, A. K., SAE-TAN, S., SUH, N. (2015). Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats. Molecular Carcinogenesis, 54(9), 916–925.
DEPARTAMENTO DE INFORMÁTICA DO SUS (DATASUS). Dados de mortalidade. Disponível em: <http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def>. Acesso em 20 mar. 2019.
DESAI, A., MITCHISON, T.J. (1997). Microtubule polymerization dynamics. Annu. Rev.
Cell Dev. Biol. 13: 83-117.
DHOUIB, I.E., JALLOULI M., ANNABI, A., GHARBI, N., ELFAZAA, S., LASRAM, M.M. (2016). A minireview on N-acetylcysteine: An old drug with new approaches. Life Sci. 151: 359–363, doi: 10.1016/ j.lfs.2016.03.003
DINICOLA, S., FUSO, A., CUCINA, A., SANTIAGO-REYES, M., VERNA, R., UNFER, V., BIZZARRI, M. (2018). Natural products - alpha-lipoic acid and acetyl-L-carnitine - in the treatment of chemotherapy-induced peripheral neuropathy. European Review for Medical and Pharmacological Sciences, 22(14), 4739–4754.
DIXON, W. J. (1980). Efficient Analysis of Experimental Observations. Annual Review of
Pharmacology and Toxicology, 20(1), 441–462.
DOZIO, E., RUSCICA, M., PASSAFARO, L., DOGLIOTTI, G., STEFFANI, L., PAGANI, A., MAGNI, P. (2010). The natural antioxidant alpha-lipoic acid induces p27Kip1-dependent
47
cell cycle arrest and apoptosis in MCF-7 human breast cancer cells. European Journal of Pharmacology, 641(1), 29–34.
DUGGETT, NA., GRIFFITHS, LA., MCKENNA, OE., DE SANTIS, V.,
YONGSANGUANCHAI, N., MOKORI, EB., FLATTERS, SJL. (2016). Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy. Neuroscience. 333:13–26.
ELBINI HOUIB, I., JALLOULI, M., ANNABI, A., GHARBI, N., ELFAZAA,
S., LASRAM, M.M. (2016). A minireview on N-acetylcysteine: An old drug with new approaches. Life Sci. Apr 15;151:359-363. doi: 10.1016/j.lfs.2016.03.003. Epub 2016 Mar 2.
ELLIS, A., BENNETT, D.L. (2013) Neuroinflammation and the generation of neuropathic pain. Br J Anaesth. 111(1):26-37.
FIDANBOYLU, M., GRITTITHS, L. A., & FLATTERS, S. J. L. (2011). Global Inhibition of Reactive Oxygen Species (ROS) Inhibits Paclitaxel-Induced Painful Peripheral Neuropathy, 6(9).
FIDLER, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews Cancer, 3, 1–6.
FITZMAURICE. ET AL. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990-2016. JAMA Oncology, v. 98121, 2018. Disponível em: http://oncology.jamanetwork.com/article.aspx?doi=10.1001/jamaoncol.2018
FRUEHRAUF, J. P. & MEYSKENS, F. L. (2007). Reactive oxygen species: a breath of life or death? Clin. Cancer Res. 13, 789–794.
G. MELLI, M. TAIANA, F. CAMOZZI, D. TRIOLO, P. PODINI, A. QUATTRINI, F. TARONI, G. LAURIA. (2008). Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy, Exp. Neurol. 214. 276–284
GALUPPO, L.F, DOS REIS LÍVERO, F.A, MARTINS, G.G, CARDOSO,
C.C, BELTRAME, O.C, KLASSEN, L.M, CANUTO, A.V, ECHEVARRIA, A, TELLES, J.E, KLASSEN, G, ACCO, A. (2016). Sydnone 1: A Mesoionic Compound with Antitumoral and Haematological Effects In Vivo. Basic Clin Pharmacol Toxicol. 2016 Jul;119(1):41-50. doi: 10.1111/bcpt.12545. Epub 2016 Jan 25.
GOTTSCHALK, A., SMITH, D.S. (2001). New Concepts in Acute Pain Therapy: Preemptive Analgesia. Am Fam Physician. May 15;63(10):1979-1985.
GREENLEE, H., HERSHMAN, D.L., SHI, Z., KWAN, M.L., et al. (2016) BMI, Lifestyle Factors and Taxane-Induced Neuropathy in Breast Cancer Patients: The Pathways Study. J Natl Cancer Inst; 109.
GUO, Y., JONES, D., LYNN PALMER, J., FORMAN, A., DAKHIL, S. R., VELASCO, M. R., … FISCH, M. (2014). Oral Alpha-Lipoic Acid to Prevent Chemotherapy-Induced
48
Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Trial HHS. Public Access. Support Care Cancer, 22(5), 1223–1231.
GUTIÉRREZ-GUTIÉRREZ, G., SERENO, M., MIRALLES, A., CASADO-SÁENZ, E., & GUTIÉRREZ-RIVAS, E. (2010). Chemotherapy-induced peripheral neuropathy: Clinical features, diagnosis, prevention and treatment strategies. Clinical and Translational
Oncology, 12(2), 81–91.
HALLIWELL, B.; GUTTERIDGE, J.M.C. (1995). The definition and measurement of antioxidants in biological systems. Free Radical Biology&Medicine, v.8, n.1,p.125–126. HERSHMAN, D. L., LACCHETTI, C., DWORKIN, RH., et al. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32(18):1941-67.
HERSHMAN, D. L., UNGER, J. M., CREW, K. D., MINASIAN, L. M., AWAD, D., MOINPOUR, C. M., … ALBAIN, K. S. (2013). Randomized Double-Blind Placebo- Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy. Journal of Clinical Oncology, 31(20), 2627–2633.
INSTITUTE FOR LABORATORY ANIMAL RESEARCH. Guide for the Care and Use of Laboratory Animals. 8th edn. National Academies Press, Washington, DC, 2011.
INSTITUTO NACIONAL DO CÂNCER (INCA). O que é o câncer. Disponível em: <http://www1.inca.gov.br/conteudo_view.asp?id=322>. Acesso em: 15 mar. 2019.
JASMIN, L., KOHAN, L., FRANSSEN, M., JANNI, G., & GOFF, J. R. (1998). The cold plate as a test of nociceptive behaviours: description and application to the study of chronic neuropathic and inflammatory pain models. Pain, 75, 367–382.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. Chemical structure for N- acetylcysteine. Disponível em: <https://jasn.asnjournals.org/content/15/2/251/tab-figures- data>. Acesso em: 25 mai. 2019.
KOTTSCHADE, L. A., SLOAN, J. A., MAZURCZAK, M. A., JOHNSON, D. B., MURPHY, B. P., ROWLAND, K. M., … LOPRINZI, C. L. (2012). The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Care Cancer, 1769–1777.
LABORATÓRIO DE NEUROANATOMIA FUNCIONAL DA DOR (LAND). Dor e nocicepção. Disponível em: <http://land.icb.usp.br/pb/dor-e-nocicepcao/>. Acesso em: 26 mai. 2019.
LEE, J. J., & SWAIN, S. M. (2006). Peripheral Neuropathy Induced by Microtubule- Stabilizing Agents. Journal of Clinical Oncology, 24(10), 1633–1642.
LEONETTI, C., BIROCCIO, A., GABELLINI, C., SCARSELLA, M., MARESCA, V., FLORI, E., … PICARDO, M. (2003). Alfa-tocopherol protects against cisplatin-induced
49
toxicity without interfering with antitumor efficacy. International Journal of Cancer, 104(2), 243–250.
LIN, P. C., LEE, M. Y., WANG, W. S., YEN, C. C., CHAO, T. C., HSIAO, L. T., … CHIOU, T. J. (2006). N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: Preliminary data. Supportive Care in
Cancer, 14(5), 484–487.
MAYO CLINIC. Breast cancer. Disponível em: <https://www.mayoclinic.org/diseases- conditions/breast-cancer/symptoms-causes/syc-20352470>. Acesso em: 27 abr. 2019.
MELLI, G., TAIANA, M., CAMOZZI, F., TRIOLO, D., PODINI, P., QUATTRINI, A., LAURIA, G. (2008). Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Experimental Neurology, 214(2), 276–284.
NELSON, D, L.; COX, MICHAEL, M. Princípios de bioquímica de Lehninger. Porto Alegre: Artmed, 2011. 6. ed. Porto Alegre: Artmed, 2014.
MIZUNO, M., MINATO, K., ITO, H., KAWADE, M., TERAI, H., TSUCHIDA, H. (1999) Anti-tumor polysaccharide from the mycelium of liquid cultured Agaricus blazei mill. Biochem Mol Biol Int. 1999;47:707–14.
NITIPIR, C. et al. (2018). Peripheral Neurotoxicity Induced by Taxanes, Cisplatin Oxaliplatin, Fluoropyrimidines and Vinorelbine. Revista De Chimie (REV CHIM- BUCHAREST), 69, 3427–3432.
PALUMBO, M. O, el al. (2013). Systemic cancer therapy: Achievements and challenges that lie ahead. Frontiers in Pharmacology, May, p. 1–9.
QUASTHOFF, S. and HARTUNG, H, P. (2002). Chemotherapy-Induced Peripheral Neuropathy. Journal of Neurology, 249, 9-17.
RANG, H.P., DALE, M.M., RITTER, J.M., FLOWER, R.J., HENDERSON, G. Farmacologia. 7ª ed. Rio de Janeiro: Elsevier, 2012.
RIVERA, E., & CIANFROCCA, M. (2015). Overview of neuropathy associated with taxanes for the treatmente of metastatic breast cancer, 659-670.
S.J.L. FLATTERS, G.J. BENNETT. (2006). Studies of peripheral sensory nerves in paclitaxelinduced painful peripheral neuropathy: evidence for mitochondrial dysfunction, Pain 122. 245–257. [27]
SAMUNI, Y., GOLDSTEIN, S., DEAN, O.M., BERK, M. (2013) The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 1830: 4117–4129, doi: 10.1016/j.bbagen. 2013.04.016
SCHESTATSKY, P. & NASCIMENTO, O. J.M. (2009). What do general neurologists need to know about neuropathic pain ?, 67(March), 741–749
SCHLOSS, J. M. et al. Nutraceuticals and chemotherapy induced peripheral neuropathy (CIPN): A systematic review. Clinical Nutrition: An International Journal Devoted to Clinical Nutrition and Metabolism. Austrália, v. 32, p.888-893, abr. 2013.
50
SHARP, D.J., ROGERS, G. C., and SCHOLEY, J. M. (2000). Microtubule motors in mitosis. Nature. 407, 41-47.
SIMÃO, D. A. S., et al. (2015). Chemotherapy-induced peripheral neuropathy: review for clinical practice. Rev. dor [online]. vol.16, n.3, pp.215-220. ISSN 1806-0013.
SISIGNANO, M., BARON, R., SCHOLICH, K., GEISSLINGER, G. (2014). Mechanism- based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev
Neurol.10(12):694-707.
SMITH, E.M., PANG, H., CIRRINCIONE, C., et al. (2013). Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA. 309:1359-1367.
UNIT, M. N. (2005). WENZEL 2005. α-lipoic acid induces apoptosis in human colon cancer. Apoptosis. 2005 Mar;10(2):359-68.
WOLF, S., BARTON, D., KOTTSCHADE, L., GROTHEY, A., & LOPRINZI, C. (2008). Chemotherapy-induced peripheral neuropathy: Prevention and treatment strategies. European Journal of Cancer, 44(11), 1507–1515.