Curcumina promove apoptose extrínseca em células de osteossarcoma canino

Autores

DOI:

https://doi.org/10.33448/rsd-v9i10.9231

Palavras-chave:

Citotoxicidade; D-17; Imunocitoquímica; Morte celular.

Resumo

O osteossarcoma canino é o tumor ósseo mais comum em cães. Ele apresenta intensa capacidade metastásica e a sobrevida do paciente é baixa nessa doença. A curcumina, o composto mais importante derivado da planta Curcuma longa L., tem sido amplamente estudada e mostrou efeitos antineoplásicos consideráveis contra vários tumores. Este estudo tem por objetivo identificar a ativação de proteínas específicas de vias de apoptose, sobrevivência tumoral e mau prognóstico dessa doença em células OSC da linhagem D-17. Para isso, as células foram cultivadas e tratadas com a curcumina nas concentrações de 20μM, 50 μM e 100 μM em lâminas, que foram preparadas e fixadas. Posteriormente, foi realizada a técnica de imucitoquímica, com os anticorpos anti-caspase3, anti-JNK, anti-AMPK, anti-p53, anti-AKT e anti-mTOR. Foi observado que a curcumina ativou em células de osteossarcoma canino in vitro as proteínas de morte celular caspase-3, JNK e AMPK, reduziu a expressão da proteína p53 mutada e não alterou as proteínas AKT e mTOR. Assim, verificou-se que a curcumina promove apoptose extrínseca mediada por caspase, JNK e cAMP/AMPK em células de osteossarcoma canino. Além disso, tem o potencial de melhorar o prognóstico tumoral dessa doença por inativação da p53 mutada. No entanto, ela não interfere na expressão de AKT/mTOR, relacionado a proliferação e sobrevivência tumoral. Tais resultados servirão de base para estudos futuros que analisem o efeito da curcumina in vivo nessa doença.

Referências

Amarante-Mendes G. P., & Green DR. (1999). The regulation of apoptotic cell death. Braz J Med Biol Res. 32:1053-61.

Anand P., Sundaram C., Jhurani S., Kunnumakkara A. B., & Aggarwal BB. (2008). Curcumin and cancer: an "old-age" disease with an "age-old" solution. Cancer Lett. 267:133-164.

Arnhold E. (2013). Package in the R environment for analysis of variance and complementary analyses. Brazilian Journal of Veterinary Research and Animal Science. 50(6):488-492.

Ashour A. A., Abdel-Aziz A. A., Mansour A. M., Alpay S. N., Huo L., & Ozpolat B. (2014). Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic câncer cells. Apoptosis. 19:241-258.

Balasubramanian S., & Eckert R. L. (2007). Curcumin suppresses AP1 transcription factor-dependent differentiation and activates apoptosis in human epidermal keratinocytes. J. Biol. Chem. 282:6707-6715.

Behrens A., Jochum W., Sibilia M., & Wagner E. F. (2000). Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. Oncogene. 19(22):2657.

Cavalcanti J. N., Amstalden E. M. I., Guerra J. L., & Magna L. C. (2004). Osteossarcoma em cães: estudo clínico-morfológico e correlação prognóstica. Brazilian Journal of Veterinary Research and Animal Science. 41(5):299- 305.

Chin K. V., Yang W. L., Ravatn R., Kita T., Reitman E., Vettori D., Cvijic M. E., Shin M., & Iacono L. (2002). Reinventing the wheel of cyclic AMP: novel mechanisms of cAMP signaling. Ann N Y Acad Sci. 968:49-64.

Collett G. P., & Campbell F. C. (2004). Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis. 25(11):183-2189.

De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D. U., Jin, R., Jones, J., & Franzoso, G. (2001). Induction of gadd45 β by NF-κ B downregulates pro-apoptotic JNK signalling. Nature. 414(6861):308-313.

Fan, T. J., Han, L. H., Cong, R. S., & Liang, J. (2005). Caspase family proteases and apoptosis. Acta biochimica et biophysica Sinica. 37(11):719-727.

Fedchenko N., & Reifenrath J. (2014). Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue–a review. Diagnostic pathology. 9(1):221.

Fitzgibbons P. L., Dillon D. A., Alsabeh R., Berman M. A., Hayes D. F., Hicks D. G., Hughes K. S., & Nofech-Mozes S. (2014). Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Arch Pathol Lab Med. 138:595-601.

Fridman J. S., & Lowe S. W. (2003). Control of apoptosis by p53. Oncogene. 22:9030-9040.

Galluzzi, L., Kepp, O., & Kroemer, G. (2016). Mitochondrial regulation of cell death: a phylogenetically conserved control. Microbial Cell. 3(3):101.

George P. (2011). p53 how crucial is its role in cancer. Int J Curr Pharm Res. 3:19-25.

Gopal P. K., Paul M., & Paul S. (2014). Curcumin induces caspase mediated apoptosis in JURKAT cells by disrupting the redox balance. Asian Pac J Cancer Prev. 15(1):93-100.

Greenblatt M. S., Bennett W. P., & Hollstein M. (1994). Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54:4855-4878.

Guo H., Xu Y. M., Ye Z. Q., Yu J. H., & Hu X. Y. (2013). Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IκBα, c-Jun and androgen receptor. Die Pharmazie-An International Journal of Pharmaceutical Sciences, 68(6), 431-434.

Hasima, N., & Aggarwal, B. B. (2012). Cancer-linked targets modulated by curcumin. International journal of biochemistry and molecular biology. 3(4):328.

Hu S., Xu Y., Meng L., Huang L., & Sun H. (2018). Curcumin inhibits proliferation and promotes apoptosis of breast cancer cells. Experimental and therapeutic medicine. 16(2):1266-1272.

Itahana K., Dimri G., & Campisi J. (2001). Regulation of cellular senescence by p53. Eur J Biochem. 268:2784-2791.

Jin Y., Tipoe G. L., Liong E. C., Lau T. Y. H., Fung P. C. W., & Leung K. M. (2001). Overexpression of BMP-2/4, −5 and BMPR-IA associated with malignancy of oral epithelium. Oral Oncol. 37:225-233.

Johnson A. S., Couto C. G., & Weghorst C. M. (1998). Mutation of the p53 tumor suppressor gene in spontaneously occurring osteosarcomas of the dog. Carcinogênese. 19:213-217.

Jordan B. C., Mock C. D., Thilagavathi R., & Selvam C. (2016). Molecular mechanisms of curcumin and its semisynthetic analogues in prostate cancer prevention and treatment. Life Sci. 152:135-144.

Khan, A. Q., Siveen, K. S., Prabhu, K. S., Kuttikrishnan, S., Akhtar, S., Shaar, A., & Uddin, S. (2018). Curcumin-mediated degradation of S-phase kinase protein 2 induces cytotoxic effects in human papillomavirus-positive and negative squamous carcinoma cells. Frontiers in Oncology. 8:399.

Kim E. K., & Choi E. J. (2010). Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396-405.

Kirpensteijn J., Kik M., Teske E., & Rutteman G. R. (2008). TP53 gene mutations in canine osteosarcoma. Veterinary Surgery. 37(5), 454-460.

Li J., Xiang S., Zhang Q., Wu J., Tang Q., Zhou J., Yang L., Chen Z., & Hann S. S. (2015). Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-kappaB/p65 and MUC1-C. J Exp Clin Cancer Res. 34:46.

Lim W., Jeong M., Bazer F. W., & Song G. (2016). Curcumin suppresses proliferation and migration and induces apoptosis on human placental choriocarcinoma cells via ERK1/2 and SAPK/JNK MAPK signaling pathways. Biology of reproduction. 95(4), 83-1.

Mirabello, L. J., Yeager, M., Mai, P. L., Gastier-Foster, J., Gorlick, R., Khanna, C., & Wunder, J. S. (2015). High prevalence of germline TP53 mutations in young osteosarcoma cases. 75:5574.

Moragoda L., Jaszewski R., & Majumdar A. P. (2001). Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res. 21:873-878.

National Center for Biotechnology Information. (2020). PubChem Database. Compound Summary: Curcumin. https://pubchem.ncbi.nlm.nih.gov/compound/Curcumin. Accessed June 04.

Pan, W., Yang, H., Cao, C., Song, X., Wallin, B., Kivlin, R., & Wan, Y. (2008). AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncology reports. 20(6):1553-1559.

Pereira, A. S., Shitsuka, D. M., Parreira, F. J., & Shitsuka, R. (2018). Metodologia da pesquisa científica.[e-book]. Santa Maria. Ed. UAB/NTE/UFSM. Disponível em: https://repositorio. ufsm. br/bitstream/handle/1/15824/Lic_Computacao_Metodologia-Pesquisa-Cientifica. pdf.

Prokocimer M., & Rotter V. (1994). Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages. Blood. 84:2391-3411.

Qian Y., & Chen X. (2013). Senescence regulation by the p53 protein family. Methods Mol Biol. 965:37-61.

Ray R. M., Jin S., Bavaria M. N., & Johnson L. R. (2011). Regulation of JNK activity in the apoptotic response of intestinal epithelial cells. American Journal of Physiology. 300(5):761-770.

Sappayatosok K., Maneerat Y., Swasdison S., Viriyavejakul P., Dhanuthai K., Zwang J., & Chaisri U. (2009). Expression of pro-inflammatory protein, iNOS, VEGF and COX-2 in oral squamous cell carcinoma (OSCC), relationship with angiogenesis and their clinico-pathological correlation. Med Oral Patol Oral Cir Bucal. 14:E319-E324.

Shackelford R. E., Kaufmann W. K., & Paules R. S. (1999). Cell cycle, checkpoint mechanism, and genotoxic stress. Environ Health Perspect. 107:5-24.

Szewczyk M., Lechowski R., & Zabielska K. (2015). What do we know about canine osteosarcoma treatment? Review. Veterinary Research Communications. 39(1):61-67.

Tait, S. W., & Green, D. R. (2010). Mitochondria and cell death: outer membrane permeabilization and beyond. Nature reviews Molecular cell biology. 11(9):621-632.

Tang G., Minemoto Y., Dibling B., Purcell N. H., Li Z., Karin M., & Lin A. (2001). Inhibition of JNK activation through NF-κ B target genes. Nature. 414(6861), 313-317.

Team RC. (2013). R: A language and environment for statistical computing.

Teiten M. H., Gaascht F., Cronauer M., Henry E., Dicato M., & Diederich M. (2011). Anti-proliferative potential of curcumin in androgen-dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway. Int J Oncol. 38(3):603-611.

Tomeh M. A., Hadianamrei R., & Zhao X. (2019). A review of curcumin and its derivatives as anticancer agents. International journal of molecular sciences. 20(5):1033-1058.

Torlakovic E. E., Riddell R., Banerjee D., El-Zimaity H., Pilavdzic D., Dawe P., Magliocco A., Barnes P., Berendt R., Cook D., Gilks B., Williams G., Perez-Ordonez B., Wehrli B., Swanson P. E., Otis C. N., Nielsen S., Vyberg M., & Butany J. (2010). Canadian Association of Pathologists-Association canadienne des pathologistes National Standards Committee/Immunohistochemistry: best practice recommendations for standardization of immunohistochemistry tests. Am J Clin Pathol. 133:354-365.

Tsuchiya T., Sekine K. I., Hinohara S. I., Namiki T., Nobori T., & Kaneko Y. (2000). Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. Cancer Genetics and Cytogenetics. 120(2):91–98.

Vallianou N. G., Evangelopoulos A., Schizas N., & Kazazis C. (2015). Potential anticancer properties and mechanisms of action of curcumin. Anticancer Res. 35:645-651.

Van Leeuwen, I. S., Cornelisse, C. J., Misdorp, W., Goedegebuure, S. A., Kirpensteijn, J., & Rutteman, G. R. (1997). P53 gene mutations in osteosarcomas in the dog. Cancer letters. 111(1-2):173-178.

Yang C. W., Chang C. L., Lee H. C., Chi C. W., Pan J. P., & Yang W. C. (2012). Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK pathways. BMC complementary and alternative medicine. 12(1):1-8.

Yu T., Ji J., & Guo Y. L. (2013). MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells. Biochemical and biophysical research communications. 441(1):53-58.

Yu, S., Shen, G., Khor, TO, Kim, JH, & Kong, AN (2008). A curcumina inibe Akt / alvo mamífero da sinalização da rapamicina através do mecanismo dependente da proteína fosfatase. Molecular cancer therapeutics. 7(9):2609-2620.

Zhang, C., Hao, Y., Wu, L., Dong, X., Jiang, N., Cong, B., & Zhao, X. (2018). Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma. International journal of oncology. 53(6):2531-2541.

Zhu G. H., Dai H. P., Shen Q., Ji O., Zhang Q., & Zhai Y. L. (2016). Curcumin induces apoptosis and suppresses invasion through MAPK and MMP signaling in human monocytic leukemia SHI-1 cells. Pharmaceutical biology. 54(8):1303-1311.

Zhu, G. H., Zhang, Q., Dai, H. P., Jl, O., & Shen, Q. (2013). Molecular mechanism of SHI-1 cell apoptosis induced by Puerariae Radix flavones in vitro. Zhongguo shi yan xue ye xue za zhi. 21(6):1423-1428.

Downloads

Publicado

16/10/2020

Como Citar

SOARES, N. P. .; NEPOMUCENO, L. L. .; CRUZ, V. de S. .; ARNHOLD, E. .; VIEIRA, V. de S. .; BORGES, J. C. de A. .; PEREIRA, D. K. S.; PEREIRA, K. F.; ARAÚJO, E. G. de . Curcumina promove apoptose extrínseca em células de osteossarcoma canino. Research, Society and Development, [S. l.], v. 9, n. 10, p. e7289109231, 2020. DOI: 10.33448/rsd-v9i10.9231. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/9231. Acesso em: 1 jul. 2024.

Edição

Seção

Ciências Agrárias e Biológicas