2-Methoxyestradiol combined with ascorbic acid facilitates the apoptosis of chronic myeloid leukemia cells via the microRNA-223/Fms-like tyrosine kinase 3/phosphatidylinositol-3 kinase/protein kinase B axis

References

• Zhou H, Xu R. Leukemia stem cells: the root of chronic myeloid leukemia. Protein Cell. 2015;6(6):403–412.
   PubMed Web of Science ®Google Scholar
• Burslem GM, Schultz AR, Bondeson DP, et al. Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation. Cancer Res. 2019;79:4744–4753.
   PubMed Web of Science ®Google Scholar
• Bennour A, Saad A, Sennana H. Chronic myeloid leukemia: relevance of cytogenetic and molecular assays. Crit Rev Oncol Hematol. 2016;97:263–274.
   PubMed Web of Science ®Google Scholar
• Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385:1447–1459.
   PubMed Web of Science ®Google Scholar
• Bavaro L, Martelli M, Cavo M, et al. Mechanisms of disease progression and resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: an update. Int J Mol Sci. 2019;20. DOI:10.3390/ijms20246141.
   PubMed Web of Science ®Google Scholar
• Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011;147:742–758.
   PubMed Web of Science ®Google Scholar
• Ngoi NYL, Choong C, Lee J, et al. Targeting mitochondrial apoptosis to overcome treatment resistance in cancer. Cancers (Basel). 2020;12. DOI:10.3390/cancers12030574.
   PubMed Web of Science ®Google Scholar
• Pistritto G, Trisciuoglio D, Ceci C, et al. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016;8:603–619.
   PubMedGoogle Scholar
• Valentin R, Grabow S, Davids MS. The rise of apoptosis: targeting apoptosis in hematologic malignancies. Blood. 2018;132:1248–1264.
   PubMed Web of Science ®Google Scholar
• Yalniz FF, Wierda WG. Targeting BCL2 in chronic lymphocytic leukemia and other hematologic malignancies. Drugs. 2019;79(12):1287–1304.
   PubMed Web of Science ®Google Scholar
• Fulda S. Targeting apoptosis for anticancer therapy. Semin Cancer Biol. 2015;31:84–88.
   PubMed Web of Science ®Google Scholar
• Mueck AO, Seeger H. 2-Methoxyestradiol–biology and mechanism of action. Steroids. 2010;75(10):625–631.
   PubMed Web of Science ®Google Scholar
• Leung K. 2-[methyl-(11)C]Methoxyestradiol. Molecular imaging and contrast agent database (MICAD). Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
   Google Scholar
• Li DL, Zhang J, Zhang WJ, et al. Effects of 2-methoxyestradiol on the expression of caspase-3 and survivin in chronic myelocytic leukemia K562 cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009;17:335–339.
   PubMedGoogle Scholar
• She MR, Li JG, Guo KY, et al. Requirement of reactive oxygen species generation in apoptosis of leukemia cells induced by 2-methoxyestradiol. Acta Pharmacol Sin. 2007;28:1037–1044.
   PubMed Web of Science ®Google Scholar
• Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012;1826:443–457.
   PubMed Web of Science ®Google Scholar
• Blaszczak W, Barczak W, Masternak J, et al. Vitamin C as a modulator of the response to cancer therapy. Molecules. 2019;24. DOI:10.3390/molecules24030453.
   PubMed Web of Science ®Google Scholar
• Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996;93:3704–3709.
   PubMed Web of Science ®Google Scholar
• Shenoy N, Creagan E, Witzig T, et al. Ascorbic acid in cancer treatment: let the phoenix fly. Cancer Cell. 2018;34:700–706.
   PubMed Web of Science ®Google Scholar
• Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007;104:8749–8754.
   PubMed Web of Science ®Google Scholar
• Verrax J, Stockis J, Tison A, et al. Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. Biochem Pharmacol. 2006;72:671–680.
   PubMed Web of Science ®Google Scholar
• Zhou S, Wang Y, Zhao M, et al. CdSeTe@CdS@ZnS quantum-dot-sensitized macroporous Tio2 film: a multisignal-amplified photoelectrochemical platform. Chemphyschem. 2015;16:2826–2835.
   PubMed Web of Science ®Google Scholar
• Aalami AH, Mesgari M, Sahebkar A. Synthesis and characterization of green zinc oxide nanoparticles with antiproliferative effects through apoptosis induction and microrna modulation in breast cancer cells. Bioinorg Chem Appl. 2020;2020:8817110.
   PubMed Web of Science ®Google Scholar
• Gerby B, Veiga DF, Krosl J, et al. High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells. J Clin Invest. 2016;126:4569–4584.
   PubMed Web of Science ®Google Scholar
• Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Ma Y, Cheng YF, et al. Involvement of reactive oxygen species in 2-methoxyestradiol-induced apoptosis in human neuroblastoma cells. Cancer Lett. 2011;313:201–210.
   PubMed Web of Science ®Google Scholar
• Li JJ, Tang Q, Li Y, et al. Role of oxidative stress in the apoptosis of hepatocellular carcinoma induced by combination of arsenic trioxide and ascorbic acid. Acta Pharmacol Sin. 2006;27:1078–1084.
   PubMed Web of Science ®Google Scholar
• Hao S, Jiang L, Fu C, et al. 2-Methoxyestradiol attenuates chronic-intermittent-hypoxia-induced pulmonary hypertension through regulating microRNA-223. J Cell Physiol. 2019;234:6324–6335.
   PubMed Web of Science ®Google Scholar
• Agatheeswaran S, Chakraborty S. MEF2C and CEBPA: possible co-regulators in chronic myeloid leukemia disease progression. Int J Biochem Cell Biol. 2016;77:165–170.
   PubMed Web of Science ®Google Scholar
• Hattori A, McSkimming D, Kannan N, et al. RNA binding protein MSI2 positively regulates FLT3 expression in myeloid leukemia. Leuk Res. 2017;54:47–54.
   PubMed Web of Science ®Google Scholar
• Zhong Y, Qiu RZ, Sun SL, et al. Small-molecule fms-like tyrosine kinase 3 inhibitors: an attractive and efficient method for the treatment of acute myeloid leukemia. J Med Chem. 2020;63:12403–12428.
   PubMed Web of Science ®Google Scholar
• Zhou X, Ma X, Sun H, et al. Let-7b regulates the Adriamycin resistance of chronic myelogenous leukemia by targeting AURKB in K562/ADM cells. Leuk Lymphoma. 2020;61:3451–3459.
   PubMed Web of Science ®Google Scholar
• Zhan H, Bai Y, Lv Y, et al. Pharmacological mechanism of mylabris in the treatment of leukemia based on bioinformatics and systematic pharmacology. Bioengineered. 2021;12:3229–3239.
   PubMed Web of Science ®Google Scholar
• Wang G, Yu X, Xia J, et al. MicroRNA-9 restrains the sharp increase and boost apoptosis of human acute myeloid leukemia cells by adjusting the Hippo/YAP signaling pathway. Bioengineered. 2021;12:2906–2914.
   PubMed Web of Science ®Google Scholar
• Zhou H, Jia X, Yang F, et al. miR-148a-3p suppresses the progression of acute myeloid leukemia via targeting cyclin-dependent kinase 6 (CDK6). Bioengineered. 2021;12:4508–4519.
   PubMed Web of Science ®Google Scholar
• Verenich S, Gerk PM. Therapeutic promises of 2-methoxyestradiol and its drug disposition challenges. Mol Pharm. 2010;7:2030–2039.
   PubMed Web of Science ®Google Scholar
• Darwiche W, Gomila C, Ouled-Haddou H, et al. Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia. J Exp Clin Cancer Res. 2020;39:228.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Hileman EO, Plunkett W, et al. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood. 2003;101:4098–4104.
   PubMed Web of Science ®Google Scholar
• Lin H, Jiang X, Zhu H, et al. 2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma. Tumour Biol. 2016;37:381–391.
   PubMedGoogle Scholar
• Lin HL, Liu TY, Chau GY, et al. Comparison of 2-methoxyestradiol-induced, docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species. Cancer. 2000;89:983–994.
   PubMed Web of Science ®Google Scholar
• Huang P, Feng L, Oldham EA, et al. Superoxide dismutase as a target for the selective killing of cancer cells. Nature. 2000;407:390–395.
   PubMed Web of Science ®Google Scholar
• Pani G, Colavitti R, Bedogni B, et al. Mitochondrial superoxide dismutase: a promising target for new anticancer therapies. Curr Med Chem. 2004;11:1299–1308.
   PubMed Web of Science ®Google Scholar
• Chen YY, Yeh CH, So EC, et al. Anticancer drug 2-methoxyestradiol protects against renal ischemia/reperfusion injury by reducing inflammatory cytokines expression. Biomed Res Int. 2014;2014:431524.
   PubMed Web of Science ®Google Scholar
• Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. 1979;39:663–681.
   PubMed Web of Science ®Google Scholar
• Di Tano M, Raucci F, Vernieri C, et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat Commun. 2020;11:2332.
   PubMed Web of Science ®Google Scholar
• Ngo B, Van Riper JM, Cantley LC, et al. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019;19:271–282.
   PubMed Web of Science ®Google Scholar
• Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al. O2(-) and H2O2-mediated disruption of fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell. 2017;32:268.
   PubMed Web of Science ®Google Scholar
• Mastrangelo D, Massai L, Lo Coco F, et al. Cytotoxic effects of high concentrations of sodium ascorbate on human myeloid cell lines. Ann Hematol. 2015;94:1807–1816.
   PubMed Web of Science ®Google Scholar
• Park CH, Amare M, Savin MA, et al. Growth suppression of human leukemic cells in vitro by L-ascorbic acid. Cancer Res. 1980;40:1062–1065.
   PubMed Web of Science ®Google Scholar
• Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005;102:13604–13609.
   PubMed Web of Science ®Google Scholar
• Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277–280.
   PubMed Web of Science ®Google Scholar
• Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172–183.
   PubMed Web of Science ®Google Scholar
• Zabriskie MS, Eide CA, Tantravahi SK, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26:428–442.
   PubMed Web of Science ®Google Scholar
• Ben-Neriah Y, Daley GQ, Mes-Masson AM, et al. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science. 1986;233:212–214.
   PubMed Web of Science ®Google Scholar
• Soverini S, Mancini M, Bavaro L, et al. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer. 2018;17:49.
   PubMed Web of Science ®Google Scholar
• Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8:1018–1029.
   PubMed Web of Science ®Google Scholar
• Bhaskar A, Raturi K, Dang S, et al. Current perspectives on the therapeutic aspects of chronic myelogenous leukemia. Expert Opin Ther Pat. 2014;24:1117–1127.
   PubMed Web of Science ®Google Scholar
• Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37:530–542.
   PubMed Web of Science ®Google Scholar
• Jiang G, Huang Z, Yuan Y, et al. Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells. J Hematol Oncol. 2021;14:139.
   PubMed Web of Science ®Google Scholar
• Rosti G, Castagnetti F, Gugliotta G, et al. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom? Nat Rev Clin Oncol. 2017;14:141–154.
   PubMed Web of Science ®Google Scholar
• Oberley TD, Oberley LW. Antioxidant enzyme levels in cancer. Histol Histopathol. 1997;12:525–535.
   PubMed Web of Science ®Google Scholar
• Sun Y, Oberley LW, Elwell JH, et al. Antioxidant enzyme activities in normal and transformed mouse liver cells. Int J Cancer. 1989;44:1028–1033.
   PubMed Web of Science ®Google Scholar
• Verrax J, Vanbever S, Stockis J, et al. Role of glycolysis inhibition and poly(ADP-ribose) polymerase activation in necrotic-like cell death caused by ascorbate/menadione-induced oxidative stress in K562 human chronic myelogenous leukemic cells. Int J Cancer. 2007;120:1192–1197.
   PubMed Web of Science ®Google Scholar
• Yang J, Lam EW, Hammad HM, et al. Antioxidant enzyme levels in oral squamous cell carcinoma and normal human oral epithelium. J Oral Pathol Med. 2002;31:71–77.
   PubMed Web of Science ®Google Scholar
• Vineetha RC, Hariharan S, Jaleel A, et al. L-ascorbic acid and alpha-tocopherol synergistically triggers apoptosis inducing antileukemic effects of arsenic trioxide via oxidative stress in human acute promyelocytic leukemia cells. Front Oncol. 2020;10:65.
   PubMed Web of Science ®Google Scholar
• Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–721.
   PubMed Web of Science ®Google Scholar
• Yun X, Rao W, Xiao C, et al. Apoptosis of leukemia K562 and Molt-4 cells induced by emamectin benzoate involving mitochondrial membrane potential loss and intracellular Ca(2+) modulation. Environ Toxicol Pharmacol. 2017;52:280–287.
   PubMed Web of Science ®Google Scholar
• Hileman EO, Liu J, Albitar M, et al. Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol. 2004;53:209–219.
   PubMed Web of Science ®Google Scholar
• Park S, Han SS, Park CH, et al. L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms. Int J Biochem Cell Biol. 2004;36:2180–2195.
   PubMed Web of Science ®Google Scholar
• Haneklaus M, Gerlic M, O’Neill LA, et al. miR-223: infection, inflammation and cancer. J Intern Med. 2013;274:215–226.
   PubMed Web of Science ®Google Scholar
• Agatheeswaran S, Singh S, Biswas S, et al. BCR-ABL mediated repression of miR-223 results in the activation of MEF2C and PTBP2 in chronic myeloid leukemia. Leukemia. 2013;27:1578–1580.
   PubMed Web of Science ®Google Scholar
• Xiao Y, Su C. Deng T. miR-223 decreases cell proliferation and enhances cell apoptosis in acute myeloid leukemia via targeting FBXW7. Oncol Lett. 2016;12:3531–3536.
   PubMed Web of Science ®Google Scholar
• Stamatopoulos B, Meuleman N, Haibe-Kains B, et al. microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification. Blood. 2009;113:5237–5245.
   PubMed Web of Science ®Google Scholar
• Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance. Int J Hematol. 2013;97:683–694.
   PubMed Web of Science ®Google Scholar
• Molina-Aguilar R, Montiel-Cervantes LA, Anguiano-Penaloza SV, et al. gammadelta T Cells Number, CD200, and Flt3 expression is associated with higher progression free survival in patients with chronic myeloid leukemia. Arch Med Res. 2020;51:194–203.
   PubMed Web of Science ®Google Scholar
• Li L, Piloto O, Kim KT, et al. FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells. Br J Haematol. 2007;137:64–75.
   PubMed Web of Science ®Google Scholar
• Kapoor S, Natarajan K, Baldwin PR, et al. Concurrent inhibition of pim and flt3 kinases enhances apoptosis of FLT3-ITD acute myeloid leukemia cells through increased Mcl-1 proteasomal degradation. Clin Cancer Res. 2018;24:234–247.
   PubMed Web of Science ®Google Scholar
• Bertacchini J, Heidari N, Mediani L, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015;72:2337–2347.
   PubMed Web of Science ®Google Scholar
• Li L, Qi Y, Ma X, et al. TRIM22 knockdown suppresses chronic myeloid leukemia via inhibiting PI3K/Akt/mTOR signaling pathway. Cell Biol Int. 2018;42:1192–1199.
   PubMed Web of Science ®Google Scholar
• Tu YX, Wang SB, Fu LQ, et al. Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway. Oncotarget. 2018;9:3267–3277.
   PubMedGoogle Scholar
• Zheng Q, Peng X, Yu H. Local anesthetic drug inhibits growth and survival in chronic myeloid leukemia through suppressing PI3K/Akt/mTOR. Am J Med Sci. 2018;355:266–273.
   PubMed Web of Science ®Google Scholar
• Kirches E, Warich-Kirches M. 2-methoxyestradiol as a potential cytostatic drug in gliomas? Anticancer Agents Med Chem. 2009;9:55–65.
   PubMed Web of Science ®Google Scholar
• Su X, Shen Z, Yang Q, et al. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics. 2019;9:4461–4473.
   PubMed Web of Science ®Google Scholar