Abstract
MicroRNAs are identified to take actively part in the development of different cancers. Reduced expression of tumor suppressor miRNAs leads to cancer cell development, so restoring the expression of these miRNAs can be an appropriate treatment option for cancer. Due to the heterogeneity of cancer cells, single-drug therapy often results in drug resistance. Therefore, the combination of chemotherapy with miRNA can be a powerful strategy for cancer treatment. In the current investigation, miR-34a mimic, and negative control were purchased and transfected using jetPEI reagents. Then the synergic effects of miR-34a in combination with doxorubicin were investigated on cell death of acute T-cell lymphoblastic leukemia Jurkat cell line, as well as the expression of some genes including Caspase-3, Bcl-2, and p53 which are involved in apoptosis. Our outcomes showed that this combination remarkably reduced the expression of the Bcl-2 gene, the target gene of miR-34a. According to the results of the MTT assay, the survival rate was significantly decreased compared to the untreated cells. Results of the flow cytometry assay and DAPI staining demonstrated an increased apoptosis rate of Jurkat cells in combination therapy. Moreover, cell cycle arrest was observed at the G2/M phase in cells that were treated with miR-34a/doxorubicin. Most importantly, we showed that the transfection of the Jurkat cells with miR-34a increased the sensitivity of these cells to doxorubicin. Furthermore, the combination of miR-34a and doxorubicin drug effectively increased apoptosis of treated cells. Therefore, this method can be used as an impressive treatment for T-ALL.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Drobna M, Szarzyńska-Zawadzka B, Dawidowska M. T-cell acute lymphoblastic leukemia from miRNA perspective: Basic concepts, experimental approaches, and potential biomarkers. Blood Rev. 2018;32:457–72.
Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. Longo DL, editor. N Engl J Med. 2015;373:1541–52.
Litzow MR, Ferrando AA. How I treat T-cell acute lymphoblastic leukemia in adults. Blood. 2015;126:833–41.
Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30:1663–9.
Karami H, Baradaran B, Esfahani A, Estiar MA, Naghavi-Behzad M, Sakhinia M, et al. siRNA-mediated silencing of survivin inhibits proliferation and enhances etoposide chemosensitivity in acute myeloid leukemia cells. Asian Pacific J Cancer Prev. 2013;14:7719–24.
Aghaee F, Pirayesh Islamian J, Baradaran B. Enhanced radiosensitivity and chemosensitivity of breast cancer cells by 2-Deoxy-D-glucose in combination therapy. J Breast Cancer. 2012;15:141.
den Hoed MAH, Pluijm SMF, te Winkel ML, de Groot-Kruseman HA, Fiocco M, Hoogerbrugge P, et al. Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia. Haematologica. 2015;100:1564–70.
Bhojwani D, Pui C-H. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14:e205–17.
Nguyen K, Devidas M, Cheng S-C, La M, Raetz EA, Carroll WL, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia. 2008;22:2142–50.
Li H, Yang BB. Friend or foe: the role of microRNA in chemotherapy resistance. Acta Pharmacol Sin. 2013;34:870–9.
Kachalaki S, Ebrahimi M, Mohamed Khosroshahi L, Mohammadinejad S, Baradaran B. Cancer chemoresistance; biochemical and molecular aspects: a brief overview. Eur J Pharm Sci. 2016;89:20–30.
Carvalho C, Santos R, Cardoso S, Correia S, Oliveira P, Santos M, et al. Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem. 2009;16:3267–85.
Sugimoto K, Tamayose K, Sasaki M, Hayashi K, Oshimi K. Low-dose doxorubicin-induced necrosis in Jurkat cells and its acceleration and conversion to apoptosis by antioxidants. Br J Haematol. 2002;118:229–38.
Miao M, Ji X, Zhang H, Xu J, Zhu H, Shao X. miR-590 promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia by inhibiting RB1. Oncotarget. 2016;7:39527–34.
Mohammadi A, Mansoori B, Baradaran B. The role of microRNAs in colorectal cancer. Biomed Pharmacother. 2016;84:705–13.
Hemmatzadeh M, Mohammadi H, Karimi M, Musavishenas MH, Baradaran B. Differential role of microRNAs in the pathogenesis and treatment of Esophageal cancer. Biomed Pharmacother. 2016;82:509–19.
Mavrakis KJ, Van Der Meulen J, Wolfe AL, Liu X, Mets E, Taghon T, et al. A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet. 2011;43:673–8.
Renou L, Boelle P-Y, Deswarte C, Spicuglia S, Benyoucef A, Calvo J, et al. Homeobox protein TLX3 activates miR-125b expression to promote T-cell acute lymphoblastic leukemia. Blood Adv. 2017;1:733–47.
Wallaert A, Van Loocke W, Hernandez L, Taghon T, Speleman F, Van Vlierberghe P. Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing. Sci Rep. 2017;7:7901.
Farooqi A, Tabassum S, Ahmad A. MicroRNA-34a: A versatile regulator of myriads of targets in different cancers. Int J Mol Sci. 2017;18:2089.
Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, et al. Mir-34: a new weapon against cancer? Mol Ther - Nucleic Acids. 2014;3:e195.
Zhang L, Liao Y, Tang L. MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. J Exp Clin Cancer Res. 2019;38:53.
van Beijnum JR, Giovannetti E, Poel D, Nowak-Sliwinska P, Griffioen AW. miRNAs: micro-managers of anticancer combination therapies. Angiogenesis. 2017;20:269–85.
Jian C, Tu M-J, Ho PY, Duan Z, Zhang Q, Qiu J-X, et al. Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models. Oncotarget. 2017;8:30742–55.
Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. Bernhard EJ, editor. PLoS One. 2009;4:e6816.
Marques SC, Ranjbar B, Laursen MB, Falgreen S, Bilgrau AE, Bødker JS, et al. High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma. Exp Hematol. 2016;44:238-246.e2.
Karrman K, Johansson B. Pediatric T-cell acute lymphoblastic leukemia. Genes, Chromosom Cancer. 2017;56:89–116.
Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017;129:1134–42.
Mansoori B, Mohammadi A, Shirjang S, Baradaran B. Micro-RNAs: The new potential biomarkers in cancer diagnosis, prognosis and cancer therapy. Cell Mol Biol (Noisy-le-grand) [Internet]. 2015;61:1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26475381
Vera J, Lai X, Schmitz U, Wolkenhauer O. MicroRNA-Regulated Networks: The Perfect Storm for Classical Molecular Biology, the Ideal Scenario for Systems Biology. 2013. p. 55–76.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.
Ogawa T, Saiki Y, Shiga K, Chen N, Fukushige S, Sunamura M, et al. miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis. Cancer Sci. 2012;103:1737–43.
Li X, Ji M, Zhong S, Zha Q, Xu J, Zhao J, et al. MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1. Arch Med Res. 2012;43:514–21.
Wang X, Dong K, Gao P, Long M, Lin F, Weng Y, et al. microRNA-34a sensitizes lung cancer cell lines to ddp treatment independent of p53 status. Cancer Biother Radiopharm. 2013;28:45–50.
Flanagan L, Meyer M, Fay J, Curry S, Bacon O, Duessmann H, et al. Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach. Cell Death Dis. 2016;7:e2087–e2087.
Végran F, Boidot R, Oudin C, Riedinger J-M, Bonnetain F, Lizard-Nacol S. Overexpression of Caspase-3s splice variant in locally advanced breast carcinoma is associated with poor response to neoadjuvant chemotherapy. Clin Cancer Res. 2006;12:5794–800.
Anagnostou VK, Lowery FJ, Zolota V, Tzelepi V, Gopinath A, Liceaga C, et al. High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology. BMC Cancer. 2010;10:186.
Lamers F, Schild L, den Hartog IJM, Ebus ME, Westerhout EM, Ora I, et al. Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer. 2012;48:3093–103.
Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170:1062–78.
Zenz T, Mohr J, Eldering E, Kater AP, Bühler A, Kienle D, et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood. 2009;113:3801–8.
Mraz M, Malinova K, Kotaskova J, Pavlova S, Tichy B, Malcikova J, et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia. 2009;23:1159–63.
Acknowledgements
We thank the research staff at the Immunology Research Center, Tabriz University of Medical Sciences for assistance in performing experiments.
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SN, and BB devised the main conceptual ideas and participated in the design of the work. BB provided biological materials and reagents. SN, BM, FV, AM, and MAD performed the experiments. SN, and KH wrote the initial draft of the manuscript. SN, BM, VK, and RM participated in the analysis of the work and reviewed and edited the manuscript. BB, and RM supervised the study.
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Najjary, S., Mohammadzadeh, R., Mansoori, B. et al. Combination therapy with miR-34a and doxorubicin synergistically induced apoptosis in T-cell acute lymphoblastic leukemia cell line. Med Oncol 38, 142 (2021). https://doi.org/10.1007/s12032-021-01578-8
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DOI: https://doi.org/10.1007/s12032-021-01578-8