Efeito do tratamento com ácido fólico e carboplatina na viabilidade de células não tumorais
DOI:
https://doi.org/10.24215/18536387e094Palavras-chave:
micronutientes, agentes quimioterápicos, viabilidade celularResumo
As células cancerígenas são altamente adaptadas e muitas vezes resistentes a agentes antitumorais, o que impede uma terapia eficaz contra o câncer. Porém, nessas células existem fatores que podem modificar a resposta ao tratamento quimioterápico. Resultados anteriores, obtidos em células tumorais HeLa, demonstraram que o ácido fólico (AF) combinado com a carboplatina (CBP) permitiu diminuir a dose de CBP utilizada e aumentar a atividade do composto de platina. Nesse sentido, é fundamental avaliar os efeitos do referido tratamento nas células saudáveis. Por esta razão, o efeito do tratamento combinado com AF e CBP in vitro na viabilidade celular (ensaio MTT) foi analisado utilizando sangue periférico de mulheres saudáveis. Os cultivos foram realizados por 48 horas a 37°C, e nas últimas 24 horas foram realizados os tratamentos: 1. controle negativo (CN); 2. controle de AF (900 nM); 3. controle de CBP (40,4 mM); 4. controle de manitol (ML 40,4 mM); 5. AF-CBP combinado (900 nM-40,4 mM); 6. AF-ML combinado (900 nM-40,4 mM); 7. controle positivo (etanol CP 10%). As culturas que receberam a combinação AF-CBP apresentaram viabilidade semelhante à observada para CN. Pelo contrário, nas culturas que receberam tratamento apenas com CBP, a viabilidade diminuiu de forma estatisticamente significativa em comparação com o referido controle. Esses achados poderiam ser uma contribuição ao explorar o uso de AF em protocolos baseados em agentes de platina, a fim de reduzir doses no tratamento de pacientes e o aparecimento de efeitos colaterais.
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Referências
Barata, F. (2008). Pemetrexed em segunda linha no carcinoma do pulmão de não pequenas células [Pemetrexed de segunda línea en el carcinoma pulmonar de células no pequeñas]. Revista Portuguesa de Pneumonología, 14(2), S21-26. https://doi.org/10.1016/S0873-2159(15)30311-1
Batra, V. y Devasagayam, T. P. A. (2009). Interaction between cytotoxic effects of γ-radiation and folate deficiency in relation to choline reserves. Toxicology, 255(1-2), 91-99. https://doi.org/10.1016/j.tox.2008.10.008
Ceresoli, G. L., Zucali, P. A., Favaretto, A. G., Grossi, F., Bidoli, P., Del Conte, G., Ceribelli, A., Bearz, A., Morenghi, E., Cavina, R., Marangolo, M., Soto Parra., H. J. y Santoro, A. (2006). Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. Journal of Clinical Oncology, 24(9), 1443-1448. https://doi.org/10.1200/JCO.2005.04.3190
Chaudhury, A., Das, S., Bunte, R. M. y Chiu, G. N. C. (2012). Potent therapeutic activity of folate receptortargeted liposomal carboplatin in the localized treatment of intraperitoneally grown human ovarian tumor xenograft. International Journal of Nanomedicine, 7, 739-751. https://doi.org/10.2147/IJN.S26172
Choi, S.-W. y Mason, J. B. (2000). Folate and carcinogenesis: An integrated scheme. The Journal of Nutrition, 130(2), 129-132. https://doi.org/10.1093/jn/130.2.129
Cohen, S. M. y Lippard, S. J. (2001). Cisplatin: From DNA damage to cancer chemotherapy. Progress in Nucleic Acid Research and Molecular Biology, 67, 93-130. https://doi.org/10.1016/s0079-6603(01)67026-0
Concha-Cisternas, Y., Martínez-Sanguinetti, M. A., Leiva, A. M., Garrido-Méndez, A., Matus-Castillo, C., Díaz-Martínez, X., Salas, C., Ramírez-Alarcón, K., Martorell, M., Cigarroa, I., Lassare-Laso, N., Troncoso, C., de Moraes Ferrari, G. L., Labraña, A. M., Parra, S., Petermann-Rocha, F. y Celis-Morales, C. (2020). Nivel de actividad física y sedentarismo en personas con diagnóstico de cáncer en Chile. Revista Médica de Chile, 148(2), 168-177. http://dx.doi.org/10.4067/s0034-98872020000200168
Conklin, K. A. (2000). Dietary antioxidants during cancer chemotherapy: Impact on chemotherapeutic effectiveness and development of side effects. Nutrition and Cancer, 37(1), 1-18. https://doi.org/10.1207/S15327914NC3701_1
Fenech, M. F. (2010). Dietary reference values of individual micronutrients and nutriomes for genome damage prevention: current status and a road map to the future. The American Journal of Clinical Nutrition, 91(5), 1438S-1454S. https://doi.org/10.3945/ajcn.2010.28674D
Gambaro, R. C, Seoane, A. y Padula G. (2023). Vitamin E protective effects on genomic and cellular damage caused by pediatric preventive supplementation for anaemia: An experimental model. British Journal of Nutrition, 129(3), 468-477. https://doi.org/10.1017/S0007114522001556
Garin, A., Manikhas, A., Biakhov, M., Chezhin, M., Ivanchenko, T., Krejcy, K., Karaseva, V. y Tjulandin, S. (2008). A phase II study of pemetrexed and carboplatin in patients with locally advanced or metastatic breast cancer. Breast Cancer Research and Treatment, 110(2), 309-315. https://doi.org/10.1007/s10549-007-9722-5
Gröber, U., Holzhauer, P., Kisters, K., Holick, M. F. y Adamietz, I. A. (2016). Micronutrients in oncological intervention. Nutrients, 8(3), 163. https://doi.org/10.3390/nu8030163
Hansen, M. F., Greibe, E., Skovbjerg, S., Rohde, S., Kristensen, A. C. M., Jensen T. R., Stentford, C., Kjær, K. H., Kronborg, C. S. y Martensen, P. M. (2015). Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha. Cellular Signalling, 27(7), 1356-1368. https://doi.org/10.1016/j.cellsig.2015.03.020
Ho, G.-Y., Woodward, N. y Coward, J. I. G. (2016). Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies. Critical Reviews in Oncology/Hematology, 102, 37-46. https://doi.org/10.1016/j.critrevonc.2016.03.014
Ji, J., Zuo, P. y Wang, Y.-L. (2015). Enhanced antiproliferative effect of carboplatin in cervical cancer cells utilizing folate-grafted polymeric nanoparticles. Nanoscale Research Letters, 10, 453. https://doi.org/10.1186/s11671-015-1162-2
Keys, H. M., Bundy, B. N., Stehman, F. B., Muderspach, L. I., Chafe, W. E., Suggs, C. L., III., Walker, J. L. y Gersell, D. (1999). Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. The New England Journal of Medicine, 340(15), 1154-1161. https://doi.org/10.1056/nejm199904153401503
Kimura, M., Umegaki, K., Higuchi, M., Thomas, P. y Fenech, M. (2004). Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytes. The Journal of Nutrition, 134(1), 48-56. https://doi.org/10.1093/jn/134.1.48
Ledermann, J. A., Canevari, S. y Thigpen, T. (2015). Targeting the folate receptor: Diagnostic and therapeutic approaches to personalize cancer treatments. Annals of Oncology, 26(10), 2034-2043. https://doi.org/10.1093/annonc/mdv250
Liu, Y., Pu, Y., Sun, L., Yao, H., Zhao, B., Zhang, R. y Zhang, Y. (2016). Folic acid functionalized γ-cyclodextrin C₆₀, a novel vehicle for tumor-targeted drug delivery. Journal of Biomedical Nanotechnology, 12(7), 1393-1403. https://doi.org/10.1166/jbn.2016.2275
Lokich, J. y Anderson, N. (1998). Carboplatin versus cisplatin in solid tumors: an analysis of the Literature. Annals of Oncology, 9(3), 13-21.
Luangwattananun, P., Chiraphapphaiboon, W., Thuwajit, C., Junking, M. y Yenchitsomanus, P.-T. (2022). Activation of cytotoxic T lymphocytes by self-differentiated myeloid-derived dendritic cells for killing breast cancer cells expressing folate receptor Alpha protein. Bioengineered, 13(6), 14188-14203. https://doi.org/10.1080/21655979.2022.2084262
Moore, K. N., Herzog, T. J., Lewin, S., Giuntoli, R. L., Armstrong, D. K., Rocconi, R. P., Spannuth, W. A. y Gold, A. M. (2007). A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer. Gynecologic Oncology, 105(2), 299-303. https://doi.org/10.1016/j.ygyno.2006.12.031
Morris, M., Eifel, P. J., Lu, J., Grigsby, P. W., Levenback, C., Stevens, R. E., Rotwan, M., Gershenson, D. M. y Mutch, D. G. (1999). Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. The New England Journal of Medicine, 340(15), 1137-1143. https://doi.org/10.1056/nejm199904153401501
Muggia, F. M. (1989). Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Seminars in Oncology, 16(2 Suppl. 5), 7-13.
Nikoloff, N., Ponzinibbio, M. V., Padula, G., De Luca, J. C., Golijow, C. D. y Seoane, A. (2016). Folic acid enhances the apoptotic and genotoxic activity of carboplatin in HeLa cell line. Toxicology in Vitro, 37, 142-147. https://doi.org/10.1016/j.tiv.2016.09.019
Organización Mundial de la Salud. (10 de agosto de 2024). Cáncer. https://www.who.int/es/healthtopics/cancer#tab=tab_1
Organización Mundial de la Salud. (10 de agosto de 2024). Cáncer cervicouterino. https://www.who.int/es/health-topics/cervical-cancer#tab=tab_1
Pett, M. y Coleman, N. (2007). Integration of high-risk human papillomavirus: A key event in cervical carcinogenesis? The Journal of Pathology, 212(4), 356-367. https://doi.org/10.1002/path.2192
Rose, P. G., Bundy, B. N., Watkins, E. B., Thigpen, J. T., Deppe, G., Maiman, M. A., Clarke-Pearson, D. L. y Insalaco, S. (1999). Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. The New England Journal of Medicine, 340(15), 1144-1153. https://doi.org/10.1056/nejm199904153401502
Shen, D.-W., Pouliot, L. M., Hall, M. D. y Gottesman, M. M. (2012). Cisplatin resistance: A cellular selfdefense mechanism resulting from multiple epigenetic and genetic changes. Pharmacological Reviews, 64(3), 706-721. https://doi.org/10.1124/pr.111.005637
Simon, G. R., Manegold, C., Barker, S. S., Treat, J. A., Visseren-Grul, C. y Obasaju C. (2013). Pemetrexed use in the adjuvant setting for completely resectable non-small-cell lung cancer. Clinical Lung Cancer, 14(6), 601-608. https://doi.org/10.1016/j.cllc.2013.06.001
Singh, N., Baldi, M., Kaur, J., Muthu, V., Prasad, K. T., Behera, D., Bal, A., Gupta, N. y Kapoor R. (2019). Timing of folic acid/vitamin B12 supplementation and hematologic toxicity during first-line treatment of patients with nonsquamous non-small cell lung cancer using pemetrexed-based chemotherapy: The PEMVITASTART randomized trial. Cancer, 125(13), 2203-2212. https://doi.org/10.1002/cncr.32028
Stratgraphics (version 5.1). (1994). Stratgraphics User Manual. Manugistics Inc.
Ströhle, A., Zänker, K. y Hahn, A. (2010). Nutrition in oncology: The case of micronutrients (Review). Oncology Reports, 24(4), 815-828. https://doi.org/10.3892/or.2010.815
Szefler, B., Czeleń, P. y Krawczyk, P. (2021). The affinity of carboplatin to B-vitamins and nucleobases. International Journal of Molecular Sciences, 22(7), 3634. https://doi.org/10.3390/ijms22073634
Wang, J. (2020). Combination treatment of cervical cancer using folate-decorated, pH-sensitive, carboplatin and paclitaxel co-loaded lipid-polymer hybrid nanoparticles. Drug Design, Development and Therapy, 14, 823-832. https://doi.org/10.2147/DDDT.S235098
Whiteside, M. A., Heimburger, D. C. y Johanning, G. L. (2004). Micronutrients and cancer therapy. Nutrition Reviews, 62(4), 142-147. https://doi.org/10.1111/j.1753-4887.2004.tb00036.x
Whitney, C. W., Sause, W., Bundy, B. N., Malfetano, J. H., Hannigan, E. V., Fowler, W. C. Jr., Clarke-Pearson, D. L. y Liao, S.-Y. (1999). Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. Journal of Clinical Oncology, 17(5), 1339-1348. https://doi.org/10.1200/jco.1999.17.5.1339
Wu, J., Lyons, G. H., Graham, R. D. y Fenech, M. F. (2009). The effect of selenium, as selenomethionine, on genome stability and cytotoxity in human lymphocytes measured using the cytokinesis-block micronucleus cytome assay. Mutagenesis, 24(3), 225-232. https://doi.org/10.1093/mutage/gen074
Xia, W. y Low, P. S. (2010). Folate-targeted therapies for cancer. Journal of Medicinal Chemistry, 53(19), 6811-6824. https://doi.org/10.1021/jm100509v
Young, O., Ngo, N., Lin, L., Stanbery, L., Creeden, J. F., Hamouda, D. y Nemunaitis, J. (2023). Folate receptor as a biomarker and therapeutic target in solid tumors. Current Problems in Cancer, 47(1), 100917. https://doi.org/10.1016/j.currproblcancer.2022.100917
Zhang, Q. I., Xiang, G., Zhang, Y., Yang, K., Fan, W. O., Lin, J., Zeng, F. y Wu, J. (2006). Increase of doxorubicin sensitivity for folate receptor positive cells when given as the prodrug N-(phenylacetyl) doxorubicin in combination with folate-conjugated PGA. Journal of Pharmaceutical Sciences, 95(10), 2266-2275. https://doi.org/10.1002/jps.20714
Zhang, G.-Z., Jiao, S.-C. y Meng, Z.-T. (2010). Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. Journal of Experimental & Clinical Cancer Research, 29, 38. https://doi.org/10.1186/1756-9966-29-38
Zinner, R. G., Fossella, F. V., Gladish, G. W., Glisson, B. S., Blumenschein, G. R. Jr., Papadimitrakopoulou, V. A., Pisters, K. M. W., Kim, E. S., Oh, Y. W., Peeples, B. O., Zhishen, Y., Curiel, R. E., Obasaju, C. K., Hong, W. K. y Herbst, R. S. (2005). Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer. Cancer, 104(11), 2449-2456. https://doi.org/10.1002/cncr.21480
Zur Hausen, H. (1996). Papillomavirus infections—a major cause of human cancers. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 1288(2), F55-F78. https://doi.org/10.1016/0304-419x(96)00020-0
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