Antileukemia Activity of Human Natural Killer Cell-Derived Nanomagic Bullets against Acute Myeloid Leukemia (AML)
,
Abstract
Background: Cancer is among the serious health problems of the medical world, for treatment of which severe treatments are used. However, the prognosis of cancer patients is still poor. The application of NK cell-derived exosomes (NK-Exo) is a new method for cancer immunotherapy. These nanoparticles with a size range of 30-120 nm are a small model of mother cells. In this study, the anti-tumor activity of NK-Exo and LAK-Exo (activated NK cell-derived exosome) against acute myeloid leukemia (AML) is investigated in vitro.
Materials and Methods: The MACS method was performed for the separation of NK cells from the buffy coats of healthy donors, and an EXOCIBE kit was used for the isolation of NK-Exo. After treating the KG-1 cell line with different doses of NK-Exo, MTT assay, and annexin V-PE were done to evaluate cell proliferation and apoptosis, respectively, and for confirmation of involved proteins, Real-Time PCR and western blotting were performed.
Results: Anti-tumor activity of NK-Exo and LAK-Exo was dose- and time-dependent. Their highest activities were observed following 48 hours of incubation with 50 µg/ml exosome (p<0.0001). However, this cytotoxic activity was also seen over a short period of time with low concentrations of NK-Exo (p<0.05) and LAK-Exo (p<0.001). The cytotoxic effect of LAK-Exo on target cells was significantly higher than NK-EXO. The induction of apoptosis by different pathways was time-point dependent. Total apoptosis was 34.56% and 51.6% after 48 hours of tumor cell coculture with 50µg/ml NK-Exo and LAK-Exo, respectively. Significant expression of CASPASE3, P38, and CYTOCHROME C genes was observed in the cells treated with 50 µg/ml NK-Exo and LAK-Exo.
Conclusion: Our study confirmed the antileukemia activity of NK-Exo against AML tumor cells in vitro. Therefore, NK-Exo can be considered as a promising and effective treatment for leukemia therapy.
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6. Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7(5):1016-1036.
7. Cruz FD, Matushansky I. Solid tumor differentiation therapy–is it possible? Oncotarget. 2012;3(5):559-567.
8. Cameron AC, Touyz RM, Lang NN. Vascular complications of cancer chemotherapy. Can J Cardiol. 2016;32(7):852-62.
9. Cordelli DM, Masetti R, Zama D, et al. Central nervous system complications in children receiving chemotherapy or hematopoietic stem cell transplantation. Front Pediatr. 2017;5:105.
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11. Zonneveld MI, Keulers TG, Rouschop K. Extracellular vesicles as transmitters of hypoxia tolerance in solid cancers. Cancers (Basel). 2019;11(2):154.
12. Tarazona R, Lopez-Sejas N, Guerrero B, et al. Current progress in NK cell biology and NK cell-based cancer immunotherapy. Cancer Immunol Immunother. 2020; 69(5):879-899.
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14. Mehta RS, Randolph B, Daher M, et al. NK cell therapy for hematologic malignancies. Int J Hematol. 2018;107(3):262-70.
15. Lanier LL. NK cell receptors. Annu Rev Immunol. 1998;16:359-93.
16. Smyth MJ, Cretney E, Kelly JM, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501-10.
17. Cheng M, Chen Y, Xiao W, et al. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013;10(3):230-52.
18. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461-9.
19. Spits H, Bernink JH, Lanier L. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat Immunol. 2016;17(7):758-64.
20. Peppicelli S, Bianchini F, Calorini L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014;33(2-3):823-32.
21. Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al., editors. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in cancer biology; 2017: Elsevier.
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34. Vela M, Corral D, Carrasco P, et al. Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia. Cancer Lett. 2018;422:107-17.
35. Lugini L, Cecchetti S, Huber V, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol. 2012;189(6):2833-42.
36. Zhu L, Kalimuthu S, Gangadaran P, et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics. 2017;7(10):2732-2745.
37. Théry C, Amigorena S, Raposo G, et al. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006: Chapter 3:Unit 3.22.
38. Carlsten M, Björkström NK, Norell H, et al. DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells. Cancer Res. 2007;67(3):1317-25.
39. Re F, Staudacher C, Zamai L, et al. Killer cell Ig‐like receptors ligand‐mismatched, alloreactive natural killer cells lyse primary solid tumors. Cancer. 2006;107(3):640-8.
40. Alici E, Sutlu T, Björkstrand B, et al. Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components. Blood. 2008;111(6):3155-62.
41. Grimm EA, Mazumder A, Zhang H, et al. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155(6):1823-41.
42. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051-7.
43. Nayyar G, Chu Y, Cairo MS. Overcoming resistance to natural killer cell based immunotherapies for solid tumors. Fronti Oncol. 2019;9:51.
44. Parolini I, Federici C, Raggi C, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284(49):34211-22.
45. Zhang Y, Liu Y, Liu H, et al. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.
46. Pace ALD, Tumino N, Besi F, et al. Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor. Cancers (Basel). 2020;12(3):661.
47. Jong AY, Wu CH, Li J, et al. Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. J Extracell Vesicles. 2017;6(1):1294368.
48. Boyiadzis M, Hong CS, Whiteside TL. Anti-Leukemia Effects of NK Cell-Derived Exosomes. 2019. Blood;134(Supplement 1):3223.
49. Pandya PH, Murray ME, Pollok KE, et al. The immune system in cancer pathogenesis: potential therapeutic approaches. J Immunol Res. 2016;2016:4273943.
50. Zhu L, Gangadaran P, Kalimuthu S, et al. Novel alternatives to extracellular vesicle-based immunotherapy–exosome mimetics derived from natural killer cells. Artif Cells Nanomed Biotechnol. 2018;46(sup3):S166-S179.
51. Wu C-H, Li J, Li L, et al. Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells. J Extracell Vesicles. 2019;8(1):1588538.
52. Zhou F. Expression of multiple granzymes by cytotoxic T lymphocyte implies that they activate diverse apoptotic pathways in target cells. Int Rev Immunol. 2010;29(1):38-55.
53. Cullen S, Brunet M, Martin S. Granzymes in cancer and immunity. Cell Death Differ. 2010;17(4):616-23.
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55. Matoska J, Wahlstrom T, Vaheri A, et al. Tumor‐associated alpha‐2‐macroglobulin in human melanomas. Int J Cancer. 1988;41(3):359-63.
56. Smorenburg SM, Griffini P, Tiggelman A, et al. α2‐Macroglobulin is mainly produced by cancer cells and not by hepatocytes in rats with colon carcinoma metastases in liver. Hepatology. 1996;23(3):560-70.
57. Ibrahim SA, Hassan H, Götte M. Micro RNA regulation of proteoglycan function in cancer. FEBS J. 2014;281(22):5009-22.
58. Wu J, Liu T, Rios Z, et al. Heat Shock Proteins and Cancer. Trends Pharmacol Sci. 2017;38(3):226-56.
59. Rui Z, Jian‐Guo J, Yuan‐Peng T, et al. Use of serological proteomic methods to find biomarkers associated with breast cancer. Proteomics. 2003;3(4):433-9.
60. Banerjee S, Lin CFL, Skinner KA, et al. Heat shock protein 27 differentiates tolerogenic macrophages that may support human breast cancer progression. Cancer Res. 2011;71(2):318-27.
61. Miyake H, Muramaki M, Kurahashi T, et al. Expression of potential molecular markers in prostate cancer: Correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Uro Onco. 2010;28(2):145-51.
62. Beresford PJ, Jaju M, Friedman RS, et al. A role for heat shock protein 27 in CTL-mediated cell death. J Immunol. 1998;161(1):161-7.
63. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002:20:323-70.
64. Fan Z, Zhang Q. Molecular mechanisms of lymphocyte-mediated cytotoxicity. Cell Mol Immunol. 2005;2(4):259-64.
65. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12(1):9-18.
66. Terada Y, Nakashima O, Inoshita S, et al. Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK. Nephrol Dial Transplant. 1999:14 Suppl 1:45-7.
67. Son Y, Kim S, Chung HT, et al. Reactive oxygen species in the activation of MAP kinases. Methods Enzymol. 2013:528:27-48.
68. Ou L, Lin S, Song B, et al. The mechanisms of graphene-based materials-induced programmed cell death: a review of apoptosis, autophagy, and programmed necrosis. Int J Nanomedicine. 2017:12:6633-6646.
69. Shi X, Wang J, Lei Y, et al. Research progress on the PI3K/AKT signaling pathway in gynecological cancer. Mol Med Rep. 2019;19(6):4529-4535.
70. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998;95(23):13513-8.
71. Suzuki A, de la Pompa JL, Stambolic V, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998;8(21):1169-78.
72. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2009:4:127-50.
73. Shoae-Hassani A, Hamidieh AA, Behfar M, et al. NK Cell–derived Exosomes From NK Cells Previously Exposed to Neuroblastoma Cells Augment the Antitumor Activity of Cytokine-activated NK Cells. J Immunother. 2017;40(7):265-276.
74. Gotthardt D, Trifinopoulos J, Sexl V, et al. JAK/STAT cytokine signaling at the crossroad of NK cell development and maturation. Front Immunol. 2019;10:2590.
75. Medvedev AE, Johnsen AC, Haux J, et al. Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK/LAK cell-mediated cytotoxicity. Cytokine. 1997;9(6):394-404.
76. Leight JL, Wozniak MA, Chen S, et al. Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition. Mol Biol Cell. 2012;23(5):781-91.
77. Franco DL, Mainez J, Vega S, et al. Snail1 suppresses TGF-β-induced apoptosis and is sufficient to trigger EMT in hepatocytes. J Cell Sci. 2010;123(Pt 20):3467-77.
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2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
3. https://gco.iarc.fr/.
4. Bukhtoyarov OV, Samarin DM. Pathogenesis of cancer: cancer reparative trap. J Cancer Ther. 2015;6(05):399-412.
5. Ponz de Leon M, Percesepe A. Pathogenesis of colorectal cancer. Dig Liver Dis. 2000;32(9):807-21.
6. Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7(5):1016-1036.
7. Cruz FD, Matushansky I. Solid tumor differentiation therapy–is it possible? Oncotarget. 2012;3(5):559-567.
8. Cameron AC, Touyz RM, Lang NN. Vascular complications of cancer chemotherapy. Can J Cardiol. 2016;32(7):852-62.
9. Cordelli DM, Masetti R, Zama D, et al. Central nervous system complications in children receiving chemotherapy or hematopoietic stem cell transplantation. Front Pediatr. 2017;5:105.
10. Koury J, Lucero M, Cato C, et al. Immunotherapies: exploiting the immune system for cancer treatment. J Immunol Res. 2018: 2018:9585614.
11. Zonneveld MI, Keulers TG, Rouschop K. Extracellular vesicles as transmitters of hypoxia tolerance in solid cancers. Cancers (Basel). 2019;11(2):154.
12. Tarazona R, Lopez-Sejas N, Guerrero B, et al. Current progress in NK cell biology and NK cell-based cancer immunotherapy. Cancer Immunol Immunother. 2020; 69(5):879-899.
13. Alberts B JA, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Innate Immunity. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26846/.
14. Mehta RS, Randolph B, Daher M, et al. NK cell therapy for hematologic malignancies. Int J Hematol. 2018;107(3):262-70.
15. Lanier LL. NK cell receptors. Annu Rev Immunol. 1998;16:359-93.
16. Smyth MJ, Cretney E, Kelly JM, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501-10.
17. Cheng M, Chen Y, Xiao W, et al. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013;10(3):230-52.
18. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461-9.
19. Spits H, Bernink JH, Lanier L. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat Immunol. 2016;17(7):758-64.
20. Peppicelli S, Bianchini F, Calorini L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014;33(2-3):823-32.
21. Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al., editors. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in cancer biology; 2017: Elsevier.
22. Vago L, Gojo I. Immune escape and immunotherapy of acute myeloid leukemia. J Clin Invest. 2020;130(4):1552-64.
23. Montaldo E, Zotto GD, Chiesa MD, et al. Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A. 2013;83(8):702-13.
24. Ratajczak J, Wysoczynski M, Hayek F, et al. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20(9):1487-95.
25. Nomura S. Extracellular vesicles and blood diseases. Inte J Hematol. 2017;105(4):392-405.
26. Urbanelli L, Buratta S, Sagini K, et al. Exosome-based strategies for diagnosis and therapy. Recent Pat CNS Drug Discov. 2015;10(1):10-27.
27. Batrakova EV, Kim MS. Development and regulation of exosome-based therapy products. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2016;8(5):744-57.
28. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-94.
29. Benard B, Gentles AJ, Köhnke T, et al. Data mining for mutation-specific targets in acute myeloid leukemia. Leukemia. 2019;33(4):826-43.
30. Sami SA, Darwish NH, Barile AN, et al. Current and future molecular targets for acute myeloid leukemia therapy. Curr Treat Options Oncol. 2020;21(1):3.
31. Witkowski MT, Lasry A, Carroll WL, et al. Immune-Based Therapies in Acute Leukemia. Trends Cancer. 2019;5(10):604-18.
32. Cooley S, He F, Bachanova V, et al. First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv. 2019;3(13):1970-80.
33. Lee DA, Denman CJ, Rondon G, et al. Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial. Biol Blood Marrow Transplant. 2016;22(7):1290-8.
34. Vela M, Corral D, Carrasco P, et al. Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia. Cancer Lett. 2018;422:107-17.
35. Lugini L, Cecchetti S, Huber V, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol. 2012;189(6):2833-42.
36. Zhu L, Kalimuthu S, Gangadaran P, et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics. 2017;7(10):2732-2745.
37. Théry C, Amigorena S, Raposo G, et al. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006: Chapter 3:Unit 3.22.
38. Carlsten M, Björkström NK, Norell H, et al. DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells. Cancer Res. 2007;67(3):1317-25.
39. Re F, Staudacher C, Zamai L, et al. Killer cell Ig‐like receptors ligand‐mismatched, alloreactive natural killer cells lyse primary solid tumors. Cancer. 2006;107(3):640-8.
40. Alici E, Sutlu T, Björkstrand B, et al. Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components. Blood. 2008;111(6):3155-62.
41. Grimm EA, Mazumder A, Zhang H, et al. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155(6):1823-41.
42. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051-7.
43. Nayyar G, Chu Y, Cairo MS. Overcoming resistance to natural killer cell based immunotherapies for solid tumors. Fronti Oncol. 2019;9:51.
44. Parolini I, Federici C, Raggi C, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284(49):34211-22.
45. Zhang Y, Liu Y, Liu H, et al. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.
46. Pace ALD, Tumino N, Besi F, et al. Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor. Cancers (Basel). 2020;12(3):661.
47. Jong AY, Wu CH, Li J, et al. Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. J Extracell Vesicles. 2017;6(1):1294368.
48. Boyiadzis M, Hong CS, Whiteside TL. Anti-Leukemia Effects of NK Cell-Derived Exosomes. 2019. Blood;134(Supplement 1):3223.
49. Pandya PH, Murray ME, Pollok KE, et al. The immune system in cancer pathogenesis: potential therapeutic approaches. J Immunol Res. 2016;2016:4273943.
50. Zhu L, Gangadaran P, Kalimuthu S, et al. Novel alternatives to extracellular vesicle-based immunotherapy–exosome mimetics derived from natural killer cells. Artif Cells Nanomed Biotechnol. 2018;46(sup3):S166-S179.
51. Wu C-H, Li J, Li L, et al. Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells. J Extracell Vesicles. 2019;8(1):1588538.
52. Zhou F. Expression of multiple granzymes by cytotoxic T lymphocyte implies that they activate diverse apoptotic pathways in target cells. Int Rev Immunol. 2010;29(1):38-55.
53. Cullen S, Brunet M, Martin S. Granzymes in cancer and immunity. Cell Death Differ. 2010;17(4):616-23.
54. Hibbetts K, Hines B, Williams D. An overview of proteinase inhibitors. J Vet Intern Med. 1999;13(4):302-8.
55. Matoska J, Wahlstrom T, Vaheri A, et al. Tumor‐associated alpha‐2‐macroglobulin in human melanomas. Int J Cancer. 1988;41(3):359-63.
56. Smorenburg SM, Griffini P, Tiggelman A, et al. α2‐Macroglobulin is mainly produced by cancer cells and not by hepatocytes in rats with colon carcinoma metastases in liver. Hepatology. 1996;23(3):560-70.
57. Ibrahim SA, Hassan H, Götte M. Micro RNA regulation of proteoglycan function in cancer. FEBS J. 2014;281(22):5009-22.
58. Wu J, Liu T, Rios Z, et al. Heat Shock Proteins and Cancer. Trends Pharmacol Sci. 2017;38(3):226-56.
59. Rui Z, Jian‐Guo J, Yuan‐Peng T, et al. Use of serological proteomic methods to find biomarkers associated with breast cancer. Proteomics. 2003;3(4):433-9.
60. Banerjee S, Lin CFL, Skinner KA, et al. Heat shock protein 27 differentiates tolerogenic macrophages that may support human breast cancer progression. Cancer Res. 2011;71(2):318-27.
61. Miyake H, Muramaki M, Kurahashi T, et al. Expression of potential molecular markers in prostate cancer: Correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Uro Onco. 2010;28(2):145-51.
62. Beresford PJ, Jaju M, Friedman RS, et al. A role for heat shock protein 27 in CTL-mediated cell death. J Immunol. 1998;161(1):161-7.
63. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002:20:323-70.
64. Fan Z, Zhang Q. Molecular mechanisms of lymphocyte-mediated cytotoxicity. Cell Mol Immunol. 2005;2(4):259-64.
65. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12(1):9-18.
66. Terada Y, Nakashima O, Inoshita S, et al. Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK. Nephrol Dial Transplant. 1999:14 Suppl 1:45-7.
67. Son Y, Kim S, Chung HT, et al. Reactive oxygen species in the activation of MAP kinases. Methods Enzymol. 2013:528:27-48.
68. Ou L, Lin S, Song B, et al. The mechanisms of graphene-based materials-induced programmed cell death: a review of apoptosis, autophagy, and programmed necrosis. Int J Nanomedicine. 2017:12:6633-6646.
69. Shi X, Wang J, Lei Y, et al. Research progress on the PI3K/AKT signaling pathway in gynecological cancer. Mol Med Rep. 2019;19(6):4529-4535.
70. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998;95(23):13513-8.
71. Suzuki A, de la Pompa JL, Stambolic V, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998;8(21):1169-78.
72. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2009:4:127-50.
73. Shoae-Hassani A, Hamidieh AA, Behfar M, et al. NK Cell–derived Exosomes From NK Cells Previously Exposed to Neuroblastoma Cells Augment the Antitumor Activity of Cytokine-activated NK Cells. J Immunother. 2017;40(7):265-276.
74. Gotthardt D, Trifinopoulos J, Sexl V, et al. JAK/STAT cytokine signaling at the crossroad of NK cell development and maturation. Front Immunol. 2019;10:2590.
75. Medvedev AE, Johnsen AC, Haux J, et al. Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK/LAK cell-mediated cytotoxicity. Cytokine. 1997;9(6):394-404.
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| Files | ||
| Issue | Vol 18 No 2 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v18i2.15368 | |
| Keywords | ||
| Natural Killer Cell Exosomes; Leukemia Immunotherapy | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Kashani Khatib Z, Maleki A, Pourfatollah AA, Hamidieh AA, Ferdowsi S. Antileukemia Activity of Human Natural Killer Cell-Derived Nanomagic Bullets against Acute Myeloid Leukemia (AML). Int J Hematol Oncol Stem Cell Res. 2024;18(2):123-139.
