Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
권호 표지
DOI QR코드

DOI QR Code

Aptamin C enhances anti-cancer activity NK cells through the activation of STAT3: a comparative study with vitamin C

  • Tomoyo Agura (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Seulgi Shin (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Hyejung Jo (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Seoyoun Jeong (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Hyovin Ahn (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • So Young Pang (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • June Lee (Nexmos, Inc.) ;
  • Jeong-Ho Park (Nexmos, Inc.) ;
  • Yejin Kim (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Jae Seung Kang (Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine)
  • Received : 2024.05.07
  • Accepted : 2024.05.18
  • Published : 2024.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Vitamin C is a well-known antioxidant with antiviral, anticancer, and anti-inflammatory properties based on its antioxidative function. Aptamin C, a complex of vitamin C with its specific aptamer, has been reported to maintain or even enhance the efficacy of vitamin C while increasing its stability. To investigate in vivo distribution of Aptamin C, Gulo knockout mice, which, like humans, cannot biosynthesize vitamin C, were administered Aptamin C orally for 2 and 4 weeks. The results showed higher vitamin C accumulation in all tissues when administered Aptamin C, especially in the spleen. Next, the activity of natural killer (NK) cells were conducted. CD69, a marker known for activating for NK cells, which had decreased due to vitamin C deficiency, did not recover with vitamin C treatment but showed an increasing with Aptamin C. Furthermore, the expression of CD107a, a cell surface marker that increases during the killing process of target cells, also did not recover with vitamin C but increased with Aptamin C. Based on these results, when cultured with tumor cells to measure the extent of tumor cell death, an increase in tumor cell death was observed. To investigate the signaling mechanisms and related molecules involved in the proliferation and activation of NK cells by Aptamin C showed that Aptamin C treatment led to an increase in intracellular STAT3 activation. In conclusion, Aptamin C has a higher capability to activate NK cells and induce tumor cell death compared to vitamin C and it is mediated through the activation of STAT3.

Keywords

Acknowledgement

We gratefully acknowledge the funding support provided by N Therapeutics Co., Ltd., and Nexmos Inc.

References

  1. Carita AC, Fonseca-Santos B, Shultz JD, Michniak-Kohn B, Chorilli M, Leonardi GR. Vitamin C: one compound, several uses. Advances for delivery, efficiency and stability. Nanomedicine 2020;24:102117.
  2. Mescic Macan A, Gazivoda Kraljevic T, Raic-Malic S. Therapeutic perspective of vitamin C and its derivatives. Antioxidants (Basel) 2019;8:247.
  3. Takamizawa S, Maehata Y, Imai K, Senoo H, Sato S, Hata R. Effects of ascorbic acid and ascorbic acid 2-phosphate, a long-acting vitamin C derivative, on the proliferation and differentiation of human osteoblast-like cells. Cell Biol Int 2004;28:255-65. https://doi.org/10.1016/j.cellbi.2004.01.010
  4. Campos PM, Goncalves GM, Gaspar LR. In vitro antioxidant activity and in vivo efficacy of topical formulations containing vitamin C and its derivatives studied by non-invasive methods. Skin Res Technol 2008;14:376-80. https://doi.org/10.1111/j.1600-0846.2008.00288.x
  5. Swindell WR, Randhawa M, Quijas G, Bojanowski K, Chaudhuri RK. Tetrahexyldecyl ascorbate (THDC) degrades rapidly under oxidative stress but can be stabilized by acetyl zingerone to enhance collagen production and antioxidant effects. Int J Mol Sci 2021;22:8756.
  6. Yamamoto I, Tai A, Fujinami Y, Sasaki K, Okazaki S. Synthesis and characterization of a series of novel monoacylated ascorbic acid derivatives, 6-O-acyl-2-O-alpha-D-glucopyranosyl-Lascorbic acids, as skin antioxidants. J Med Chem 2002;45:462-8. https://doi.org/10.1021/jm010379f
  7. Ravetti S, Clemente C, Brignone S, Hergert L, Allemandi D, Palma S. Ascorbic acid in skin health. Cosmetics 2019; 6:58.
  8. Weeks BS, Perez PP. Absorption rates and free radical scavenging values of vitamin C-lipid metabolites in human lymphoblastic cells. Med Sci Monit 2007;13:BR205-10.
  9. Pinnell SR, Yang H, Omar M, Monteiro-Riviere N, DeBuys HV, Walker LC, Wang Y, Levine M. Topical L-ascorbic acid: percutaneous absorption studies. Dermatol Surg 2001;27:137-42.
  10. Song MK, Lee JH, Kim J, Kim JH, Hwang S, Kim YS, Kim YJ. Neuroprotective effect of NXP031 in the MPTP-induced Parkinson's disease model. Neurosci Lett 2021;740:135425.
  11. Choi S, Han J, Kim JH, Kim AR, Kim SH, Lee W, Yoon MY, Kim G, Kim YS. Advances in dermatology using DNA aptamer "Aptamin C" innovation: oxidative stress prevention and effect maximization of vitamin C through antioxidation. J Cosmet Dermatol 2020;19:970-6.
  12. Lee D, Kim Y, Jo H, Go C, Jeong Y, Jang Y, Kang D, Park K, Kim YS, Kang JS. The anti-inflammatory effect of Aptamin C on house dust mite extract-induced inflammation in keratinocytes via regulation of IL-22 and GDNF production. Antioxidants (Basel) 2021;10:945.
  13. Kong AH, Wu AJ, Ho OK, Leung MM, Huang AS, Yu Y, Zhang G, Lyu A, Li M, Cheung KH. Exploring the potential of aptamers in targeting neuroinflammation and neurodegenerative disorders: opportunities and challenges. Int J Mol Sci 2023;24:11780.
  14. Delves PJ. Innate and adaptive systems of immunity. In: Rose NR, Mackay IR, editors. The Autoimmune Diseases. 6th ed. Academic Press; 2020. p.45-61.
  15. Vivier E, Malissen B. Innate and adaptive immunity: specificities and signaling hierarchies revisited. Nat Immunol 2005;6:17-21. https://doi.org/10.1038/ni1153
  16. Khan MM. Overview of the immune response. In: Khan MM, editor. Immunopharmacology. Springer; 2016. p.1-55.
  17. Nutt SL, Huntington ND. Cytotoxic T lymphocytes and natural killer cells. In: Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM, editors. Clinical Immunology. 5th ed. Elsevier; 2019. p.247-59.e1.
  18. Guglielmo A, Zengarini C, Agostinelli C, Motta G, Sabattini E, Pileri A. The role of cytokines in cutaneous T cell lymphoma: a focus on the state of the art and possible therapeutic targets. Cells 2024;13:584.
  19. Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O'Mahony L, Palomares O, Rhyner C, Ouaked N, Schaffartzik A, Van De Veen W, Zeller S, Zimmermann M, Akdis CA. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol 2011;127:701-21.e1-70. https://doi.org/10.1016/j.jaci.2010.11.050
  20. Racke MK, Bonomo A, Scott DE, Cannella B, Levine A, Raine CS, Shevach EM, Rocken M. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 1994;180:1961-6. https://doi.org/10.1084/jem.180.5.1961
  21. Yoshimoto T, Yoshimoto T. Cytokine frontiers: regulation of immune responses in health and disease. Springer; 2013.
  22. Kim H, Jang M, Kim Y, Choi J, Jeon J, Kim J, Hwang YI, Kang JS, Lee WJ. Red ginseng and vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus/H1N1 infection. J Pharm Pharmacol 2016;68:406-20. https://doi.org/10.1111/jphp.12529
  23. Kim JH, Kim DH, Jo S, Cho MJ, Cho YR, Lee YJ, Byun S. Immunomodulatory functional foods and their molecular mechanisms. Exp Mol Med 2022;54:1-11. https://doi.org/10.1038/s12276-022-00724-0
  24. Jeong YJ, Kim JH, Hong JM, Kang JS, Kim HR, Lee WJ, Hwang YI. Vitamin C treatment of mouse bone marrow-derived dendritic cells enhanced CD8(+) memory T cell production capacity of these cells in vivo. Immunobiology 2014;219:554-64. https://doi.org/10.1016/j.imbio.2014.03.006
  25. Grudzien M, Rapak A. Effect of natural compounds on NK cell activation. J Immunol Res 2018;2018:4868417.
  26. Toliopoulos I, Simos Y, Verginadis I, Oikonomidis S, Karkabounas S. NK cell stimulation by administration of vitamin C and Aloe vera juice in vitro and in vivo: a pilot study. J Herb Med 2012;2:29-33.
  27. Huijskens MJ, Walczak M, Sarkar S, Atrafi F, Senden-Gijsbers BL, Tilanus MG, Bos GM, Wieten L, Germeraad WT. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 2015;17:613-20. https://doi.org/10.1016/j.jcyt.2015.01.004
  28. Mandl J, Szarka A, Banhegyi G. Vitamin C: update on physiology and pharmacology. Br J Pharmacol 2009;157:1097-110. https://doi.org/10.1111/j.1476-5381.2009.00282.x
  29. Carr AC, Maggini S. Vitamin C and immune function. Nutrients 2017;9:1211.
  30. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66-74. https://doi.org/10.1046/j.1523-5408.2002.00005.x
  31. Murad S, Grove D, Lindberg KA, Reynolds G, Sivarajah A, Pinnell SR. Regulation of collagen synthesis by ascorbic acid. Proc Natl Acad Sci U S A 1981;78:2879-82. https://doi.org/10.1073/pnas.78.5.2879
  32. Stone N, Meister A. Function of ascorbic acid in the conversion of proline to collagen hydroxyproline. Nature 1962;194:555-7. https://doi.org/10.1038/194555a0
  33. Davey MW, Montagu MV, Inze D, Sanmartin M, Kanellis A, Smirnoff N, Benzie IJ, Strain JJ, Favell D, Fletcher J. Plant Lascorbic acid: chemistry, function, metabolism, bioavailability and effects of processing. J Sci Food Agric 2000;80:825-60. https://doi.org/10.1002/(SICI)1097-0010(20000515)80:7<825::AID-JSFA598>3.0.CO;2-6
  34. Kim Y, Kim H, Bae S, Choi J, Lim SY, Lee N, Kong JM, Hwang YI, Kang JS, Lee WJ. Vitamin C Is an essential factor on the anti-viral immune responses through the production of interferon-α/β at the initial stage of influenza A virus (H3N2) infection. Immune Netw 2013;13:70-4. https://doi.org/10.4110/in.2013.13.2.70
  35. Jo H, Lee D, Go C, Jang Y, Chu N, Bae S, Kang D, Im JP, Kim Y, Kang JS. Preventive effect of vitamin C on dextran sulfate sodium (DSS)-induced colitis via the regulation of IL-22 and IL-6 production in Gulo(-/-) mice. Int J Mol Sci 2022;23:10612.
  36. Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition 2020;12:100190.
  37. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999;17:189-220. https://doi.org/10.1146/annurev.immunol.17.1.189
  38. Bald T, Krummel MF, Smyth MJ, Barry KC. The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nat Immunol 2020;21:835-47. https://doi.org/10.1038/s41590-020-0728-z
  39. Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol 2015;6:368.
  40. Poggi A, Zocchi MR. NK cell autoreactivity and autoimmune diseases. Front Immunol 2014;5:27.
  41. Rothlisberger P, Hollenstein M. Aptamer chemistry. Adv Drug Deliv Rev 2018;134:3-21. https://doi.org/10.1016/j.addr.2018.04.007
  42. Wu Z, Tang LJ, Zhang XB, Jiang JH, Tan W. Aptamer-modified nanodrug delivery systems. ACS Nano 2011;5:7696-9. https://doi.org/10.1021/nn2037384
  43. Iliuk AB, Hu L, Tao WA. Aptamer in bioanalytical applications. Anal Chem 2011;83:4440-52. https://doi.org/10.1021/ac201057w
  44. Song KM, Lee S, Ban C. Aptamers and their biological applications. Sensors (Basel) 2012;12:612-31. https://doi.org/10.3390/s120100612
  45. Kalathingal M, Rhee YM. Molecular mechanism of binding between a therapeutic RNA aptamer and its protein target VEGF: a molecular dynamics study. J Comput Chem 2023;44:1129-37. https://doi.org/10.1002/jcc.27070
  46. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805-16. https://doi.org/10.1056/NEJMoa042760
  47. Ng EW, Shima DT, Calias P, Cunningham ET Jr, Guyer DR, Adamis AP. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 2006;5:123-32. https://doi.org/10.1038/nrd1955
  48. Kim H, Bae S, Yu Y, Kim Y, Kim HR, Hwang YI, Kang JS, Lee WJ. The analysis of vitamin C concentration in organs of gulo(-/-) mice upon vitamin C withdrawal. Immune Netw 2012;12:18-26. https://doi.org/10.4110/in.2012.12.1.18
  49. Jung SA, Lee DH, Moon JH, Hong SW, Shin JS, Hwang IY, Shin YJ, Kim JH, Gong EY, Kim SM, Lee EY, Lee S, Kim JE, Kim KP, Hong YS, Lee JS, Jin DH, Kim T, Lee WJ. L-ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells. Free Radic Biol Med 2016;95:200-8. https://doi.org/10.1016/j.freeradbiomed.2016.03.009