Omega 3 supplementation to reduce alpha threonine kinase 1 (AKT1) levels in children with acute lymphoblastic leukemia (ALL) in the induction phase of chemotherapy
Omega 3 supplementation in children with ALL
DOI:
https://doi.org/10.59747/smjidisurabaya.v1i2.13Keywords:
omega 3, acute lymphoblastic leukemia, AKT, apoptosis, cancerAbstract
Background: Omega-3 inhibits tumor growth and progression in various cancers, but the mechanisms involved remain unclear. Omega-3 induces apoptosis, promotes cell cycle arrest, and reduces inflammation through various mechanisms, including reduced AKT phosphorylation. AKT is involved in cell growth, proliferation, and apoptosis. Acute lymphoblastic leukemia is one of the most prevalent malignancies in children with low remission levels. PI3K/AKT pathway mutations are found in acute lymphoblastic leukemia. Omega-3 is known to inhibit leukemogenesis through AKT1 signaling pathways. Objectives: To analyze omega-3’s role in AKT1 level reduction in children with acute lymphoblastic leukemia (ALL). Methods: A randomized open label pre- and post-test control group study was conducted on two groups: a treatment group receiving 1,000 mg of omega-3 orally once a day during the chemotherapy protocol’s induction phase; and a control group receiving placebos. AKT1 levels were measured before (day 0) and after the induction phase of chemotherapy was completed (day 43). The statistical analysis included paired t-tests, independent sample t-tests, and chi-square tests. Results: Twenty-six subjects included in this study were divided into 13 subjects in the control group and 13 subjects in the treatment group. There was a significant reduction in AKT levels before and after receiving omega-3 supplementation in the treatment group (p < 0.001). Meanwhile, there was a significant increase in the control group’s AKT1 levels (p< 0.001). Conclusion: Omega-3 supplementation suppressed AKT1 levels.
References
Aggarwal, B.B., Bhardwaj, A., Aggarwal, R.S., Seeram, N.P., Shishodia, S., Takada, Y., 2004. Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies, Anticancer Res. 24(5A):2783-840.
Altman, B.J., Rathmell, J.C., 2012. Metabolic stress in autophagy and cell death pathways. Cold Spring Harb. Perspect. Biol. 4(9):a008763. doi: 10.1101/cshperspect.a008763.
Bayram, I., Erbey, F., Celik, N., Nelson, J.L., Tanyeli, A., 2009. The Use of a Protein and Energy Dense Eicosapentaenoic Acid Containing Supplement for Malignancy-Related Weight Loss in Children. Pediatr Blood Cancer 52(5):571–574. doi: 10.1002/pbc.21852
Bressanin, D., Evangelisti, C., Ricci, F., Tabellini, G., Chiarini, F., Tazzari, P.L., Melchionda, F., Buontempo, F., Pagliaro, P., Pession, A., McCubrey, J.A., Martelli, A.M., 2012. Harnessing the PI3K/Akt/mtor pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels. Oncotarget 3(8):811–823. doi: 10.18632/oncotarget.579.
Chang, F., Lee, J.T., Navolanic, P.M., Steelman, L.S., Shelton, J.G., Blalock, W.L., Franklin, R.A., McCubrey, J.A., 2003. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 17(3):590–603. doi: 10.1038/sj.leu.2402824.
D’Eliseo, D., Velotti, F., 2016. Omega-3 Fatty Acids and Cancer Cell Cytotoxicity: Implications for Multi-Targeted Cancer Therapy. J. Clin. Med. 5(2):15. doi: 10.3390/jcm5020015.
Dan, H.C., Antonia, R.J., Baldwin, A.S., 2016. PI3K/Akt promotes feedforward mTORC2 activation through IKKα. Oncotarget 7(16):21064–21075. doi: 10.18632/oncotarget.8383.
DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., Thompson, C.B., 2008. The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation. Cell Metab. 7(1):11–20. doi: 10.1016/j.cmet.2007.10.002.
Elbarbary, N.S., Ismail, E.A.R., Farahat, R.K., El-Hamamsy, M., 2016. ω-3 fatty acids as an adjuvant therapy ameliorates methotrexate-induced hepatotoxicity in children and adolescents with acute lymphoblastic leukemia: A randomized placebo-controlled study. Nutrition 32(1):41–47. doi: 10.1016/j.nut.2015.06.010.
Elstrom, R.L., Bauer, D.E., Buzzai, M., Karnauskas, R., Harris, M.H., Plas, D.R., Zhuang, H., Cinalli, R.M., Alavi, A., Rudin, C.M., Thompson, C.B., 2004. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64(11):3892–3899. doi: 10.1158/0008-5472.CAN-03-2904.
FAO, 2010. Fats and fatty acids in human nutrition. Report of an expert consultation. Food and Agriculture Organization of the United Nations: Rome.
Fransecky, L., Mochmann, L.H., Baldus, C.D., 2015. Outlook on PI3K / AKT / mTOR inhibition in acute leukemia. Mol Cell Ther. 3:2. doi: 10.1186/s40591-015-0040-8. PMID: 26056603
Gu, Z., Wu, J., Wang, S., Suburu, J., Chen, H., Thomas, M.J., Shi, L., Edwards, I.J., Berquin, I.M., Chen, Y.Q., 2013. Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. Carcinogenesis 34(9):1968–1975. doi: 10.1093/carcin/bgt147.
Hegde, S., Kaushal, N., Ravindra, K.C., Chiaro, C., Hafer, K.T., Gandhi, U.H., Thompson, J.T., Van Den Heuvel, J.P., Kennett, M.J., Hankey, P., Paulson, R.F., Prabhu, K.S., 2011. Δ 12-prostaglandin J 3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice. Blood 118(26):6909–6919. doi: 10.1182/blood-2010-11-317750.
IARC, 2004. Mechanisms of Carcinogenesis: contributions of molecular epidemiology, IARC Scientific Publications. Kluwer Academic Publishers, Netherlands.
Institute of Medicine of the National Academies, 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids, National Academy of Sciences. Washington D.C.
Lobato-Mendizábal, E., Ruiz-Argüelles, G.J., Marín-López, A., 1989. Leukaemia and nutrition I: Malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard-risk acute lymphoblastic leukaemia. Leuk. Res. 13(10):899–906. doi: 10.1016/0145-2126(89)90043-x.
Martelli, A.M., Evangelisti, C., Chappell, W., Abrams, S.L., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., Nicoletti, F., Libra, M., Ruvolo, V., Ruvolo, P., Kempf, C.R., Steelman, L.S., McCubrey, J.A., 2011. Targeting the translational apparatus to improve leukemia therapy: Roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia 25(7):1064–1079. doi: 10.1038/leu.2011.46.
Möricke, A., Zimmermann, M., Reiter, A., Gadner, H., Odenwald, E., Harbott, J., Ludwig, W.D., Riehm, H., Schrappe, M., 2005. Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: Data from the trials ALL-BFM 86, 90, and 95. Klin. Padiatr. 217(6):310–320. doi: 10.1055/s-2005-872515.
Mostert, S., Sitaresmi, M.N., Gundy, C.M., Sutaryo, Veerman, A.J.P., 2006. Influence of socioeconomic status on childhood acute lymphoblastic leukemia treatment in Indonesia. Pediatrics 118(6):e1600-6. doi: 10.1542/peds.2005-3015.
Park, S., Chapuis, N., Tamburini, J., Bardet, V., Cornillet-Lefebvre, P., Willems, L., Green, A., Mayeux, P., Lacombe, C., Bouscary, D., 2010. Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. Haematologica 95(5):819–828. doi: 10.3324/haematol.2009.013797.
Piovan, E., Yu, J., Tosello, V., Herranz, D., Ambesi-Impiombato, A., DaSilva, A.C., Sanchez-Martin, M., Perez-Garcia, A., Rigo, I., Castillo, M., Indraccolo, S., Cross, J.R., deStanchina, E., Paietta, E., Racevskis, J., Rowe, J.M., Tallman, M.S., Basso, G., Meijerink, J.P., Cordon-Cardo, C., Califano, A., Ferrando, A.A., 2013. Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. Cancer Cell 24(6):766–776. doi: 10.1016/j.ccr.2013.10.022.
Rana, Z.A., Rabbani, M.W., Sheikh, M.A., Khan, A.A., 2009. Outcome of childhood Acute Lymphoblastic Leukemia after Induction Therapy — 3 Years Experience ata a single Paediatric Oncology Centre. J Ayub Med Coll Abbottabad 21(4):150–153.
Sam, M.R., Esmaeillou, M., Shokrgozar, M.A., 2017. Fish-Oil-Derived DHA-mediated Enhancement of Apoptosis in Acute Lymphoblastic Leukemia Cells is Associated with Accumulation of p53, Downregulation of Survivin, and Caspase-3 Activation. Nutr. Cancer 69(1):64–73. doi: 10.1080/01635581.2017.1247884.
Sanchez, V.E., Nichols, C., Kim, H.N., Gang, E.J., Kim, Y.M., 2019. Targeting PI3K signaling in acute lymphoblastic leukemia. Int. J. Mol. Sci. 20(2):412. doi: 10.3390/ijms20020412
Sawyer, M.B., Field, C.J., 2010. Possible Mechanisms of ω-3 PUFA Anti-tumour Action. In: Calviello, G., Serini, S. (Eds.), Dietary Omega-3 Polyunsaturated Fatty Acids and Cancer. pp. 3–38. Springer: London
Serhan, C.N., Chiang, N., 2008. Endogenous pro-resolving and anti-inflammatory lipid mediators: A new pharmacologic genus. Br. J. Pharmacol. 153 (Suppl 1):200–215. doi: 10.1038/sj.bjp.0707489.
Shin, S., Jing, K., Jeong, S., Kim, N., Song, K.S., Heo, J.Y., Park, J.H., Seo, K.S., Han, J., Park, J. Il, Kweon, G.R., Park, S.K., Wu, T., Hwang, B.D., Lim, K., 2013. The omega-3 polyunsaturated fatty acid DHA induces simultaneous apoptosis and autophagy via mitochondrial ROS-mediated Akt-mTOR signaling in prostate cancer cells expressing mutant p53. Biomed Res. Int. 2013:568671. doi: 10.1155/2013/568671.
Sitaresmi, M.N., Mostert, S., Gundy, C.M., Ismail, D., Veerman, A.J.P., 2013. A Medication Diary-Book for Pediatric Patients With Acute Lymphoblastic Leukemia in Indonesia. Pediatr. Blood Cancer 60(10):1593–1597. doi: 10.1002/pbc.24570.
Suppipat, K., Zhu, E., Lacorazza, D., 2011. Targeting AKT Signaling in Pediatric Acute Lymphoblastic Leukemia with Sulforaphane. Blood 118(21):1521. doi:10.1182/blood.V118.21.1521.1521.
Supriyadi, E., Widjajanto, P.H., Purwanto, I., Cloos, J., Veerman, A.J.P., Sutaryo, S., 2011. Incidence of Childhood Leukemia in Yogyakarta, Indonesia, 1998–2009. Pediatr. Blood Cancer 57(4):588–593. doi: 10.1002/pbc.23109.
Terwilliger, T., Abdul-Hay, M., 2017. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 7(6):e577. doi: 10.1038/bcj.2017.53.
WHO Europe, 2009. Incidence of childhood leukaemia. RPG4_Rad_E1
Wilder, J., 2015. The Role of AKT signaling in Cell Acute ymphoblastic Leukemia Relapse. Doctoral dissertation, Harvard Medical School.
Downloads
Published
Issue
Section
Categories
License
Copyright (c) 2023 Lini Delina
This work is licensed under a Creative Commons Attribution 4.0 International License.
