Alpha-Fetoprotein: A Revolutionary Anti-Cancer Drug
Main Article Content
Abstract
Alpha-fetoprotein is an oncofetal protein the embryo produces during fetal development. The protein serves two critical functions simultaneously: it delivers nutrients to growing embryo cells and immature myeloid-derived suppressor cells, so the mother’s immune system doesn’t attack the embryo. The protein is present in minuscule amounts in adults and elevated alpha-fetoprotein levels serve as pregnancy or tumor markers. Exogenous alpha-fetoprotein has a new application as an immunotherapy drug. It can deliver drugs in a natural shuttle manner to myeloid-derived suppressor cells and stimulate them to calm the hyperactive immune response during many physiological and pathological conditions. On the other hand, alpha-fetoprotein loaded with toxins kills myeloid-derived suppressor cells and unleashes natural killer cells and cytotoxic lymphocytes to erase cancer. Most cancers have cells that specifically bind alpha-fetoprotein, and this protein targets chemotherapy to them also. So, alpha-fetoprotein with toxins combines both potent cancer immunotherapy and targeted chemotherapy activities. Alpha-fetoprotein can be chemically conjugated with or bind toxins non-covalently. Both preparations have demonstrated superior efficacy and safety compared to chemotherapy alone. Alpha-fetoprotein-toxin immuno/chemotherapy is not personalized. There is no need to preselect patients for cancer treatments as they have elevated myeloid-derived suppressor cell levels. The anti-cancer efficacy of porcine alpha-fetoprotein non-covalent complexes with selected toxins administered orally is a remarkable discovery that needs research. Cancer treatment and prevention are different issues, and they could need different approaches. Alpha-fetoprotein administration with drugs or toxins could be as effective in early cancer and metastasis prevention as mifepristone pills in pregnancy prevention.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Laan-Pütsep K, Wigzell H, Cotran P, et al. Human α-fetoprotein (AFP) causes a selective down regulation of monocyte MHC class II molecules without altering other induced or noninduced monocyte markers or functions in monocytoid cell lines. Cell Immunol. 1991; 133(2):506-518. doi.org/10.1016/0008-8749(91)90122-R
3. Wang W, Alpert E. Downregulation of phorbol 12-myristate 13-acetate-induced tumor necrosis factor-α and interleukin-1β production and gene expression in human monocytic cells by human α-fetoprotein. Hepatol. 1995; 22:921-928. PMID: 7544757
4. Sedky HA, Youssef SR, Gamal DA, et al. First report of the unique expression of RECAF (receptor for alfa feto-protein) in adult B-NHL/CLL patients. BR. 2020; 55:253-261. doi.org/10.5045/br.2020.2020070
5. Suzuki Y, Zeng CQ, Alpert E. Isolation and partial characterization of a specific alpha-fetoprotein receptor on human monocytes. J Clin Invest. 1992; 90(4):1530-1536. doi: 10.1172/JCI116021
6. Mizejewski GJ. (Ed.). Biological Activities of Alpha-Fetoprotein. Vol. I and II. 1987; Boca Raton Florida Congresses: CRC Press, Inc.
7. Mizejewski GJ. Alpha-Fetoprotein Structure and Function: Relevance to Isoforms, Epitopes, and Conformational Variants. Exp Biol Med (Maywood, N.J.). 2001; 226 (5):377–408. doi.org/10.1177/153537020122600503
8. Chereshnev VA, Rodionov SYu, Sherkasov VA, et al. Alpha-fetoprotein. Russia: YuD RAS. 2004. www.biomedservice.ru/preparat/libr alfetin3.pdf
9. Terentiev AA, Moldogazieva NT. Alpha-Fetoprotein: A Renaissance. Tumour Biol. 2013; 34 (4):2075–2091. doi.org/10.1007/s13277-013-0904-y
10. Lakhi N, Moretti M. (Eds.). Alpha-Fetoprotein: Functions and Clinical Application. Protein Biochemistry, Synthesis, Structure and Cellular Functions. 2016; Hauppauge, New York: Nova Science Publisher’s, Inc. ISBN: 978-1-63484-875-6
11. Bronte VS, Brandau Sh.-H, Chen MP, et al. Recommendations for Myeloid-Derived Suppressor Cell Nomenclature and Characterization Standards. Nat Commun. 2016; 7:12150. doi.org/10.1038/ncomms12150
12. Ahmadi M, Mohammadi M, Ali-Hassanzadeh M, et al. MDSCs in Pregnancy: Critical Players for a Balanced Immune System at the Feto-Maternal Interface. Cell Immunol. 2019; 346:103990. doi.org/10.1016/j.cellimm.2019.103990
13. Köstlin-Gille N, Dietz S, Schwarz J, et al. 2019. HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice. Front Immunol. 2019; 10:161. doi.org/10.3389/fimmu.2019.00161
14. Jørgensen N, Persson G, Hviid TVF. The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer. Front Immunol. 2019; 10:911. doi.org/10.3389/fimmu.2019.00911
15. Pawelec G, Verschoor CP, Ostrand-Rosenberg S. Myeloid-Derived Suppressor Cells: Not Only in Tumor Immunity. Front Immunol. 2019; 10:1099. DOI: 10.3389/fimmu.2019.01099
16. Ostrand-Rosenberg S, Lamb TJ, Pawelec G. Here, There, and Everywhere: Myeloid-Derived Suppressor Cells in Immunology. J Immunol. 2023; 210 (9):1183–1197. doi.org/10.4049/jimmunol.2200914
17. Pak VN. The use of alpha-fetoprotein for the treatment of autoimmune diseases and cancer. Ther
Deliv. 2017; 9(1):37-46. doi: 10.4155/tde-2017-0073
18. Munson PV, Adamik J, Butterfield LH. Immunomodulatory impact of α-fetoprotein. Trends Immunol. 2022; 43(6):438-448. doi: 10.1016/j.it.2022.04.001
19. Carlsson RN, Ingvarsson BI, Karlsson BW. Isolation and Characterization of Alpha-Foetoprotein from Foetal Pigs. Int. J. Biochem. 1976; 7:13–20.
20. Yan D, Yang Q, Shi M, et al. Polyunsaturated Fatty Acids Promote the Expansion of Myeloid-Derived Suppressor Cells by Activating the JAK/STAT3 Pathway. Eur J Immunol. 2013; 43 (11):2943–2955. doi.org/10.1002/eji.201343472
21. Pak VN. Selective targeting of myeloid-derived suppressor cells in cancer patients through AFP-binding receptors. Fut Sci OA. 2018; doi.org/10.4155/fsoa-2018-0029
22. Jiménez-Cortegana C, Galassi C, Klapp V, et al. Myeloid-Derived Suppressor Cells and Radiotherapy. Cancer Immunol Res. 2022; 10(5):545-557. doi:10.1158/2326-6066.CIR-21-1105
23. Barry ST, Gabrilovich DI, Sansom OJ, et al. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer. 2023; 23:216–237. doi.org/10.1038/s41568-022-00546-2
24. Cao J, Chow L, and Dow S. Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment. Front. Oncol. 2023; 13:1116016. doi: 10.3389/fonc.2023.1116016
25. Torres JM, Geuskens M, Uriel J. Receptor-Mediated Endocytosis and Recycling of Alpha-Fetoprotein in Human B-Lymphoma and T-Leukemia Cells. Int J Can. 1991; 47 (1):110–117. doi.org/10.1002/ijc.2910470120
26. Esteban C, Trojan J, Macho A, et al. Activation of an Alpha-Fetoprotein/Receptor Pathway in Human Normal and Malignant Peripheral Blood Mononuclear Cells. Leukemia. 1993;7 (11):1807–1816. pubmed.ncbi.nlm.nih.gov/7694005
27. Esteban C, Geuskens M, Uriel J. Activation of an Alpha-Fetoprotein (AFP)/Receptor Autocrine Loop in HT-29 Human Colon Carcinoma Cells. Int J Can. 1991;49 (3):425–430. doi.org/10.1002/ijc.2910490320.
28. Mizejewski GJ. A Compendium of Ligands Reported to Bind Alpha-Fetoprotein: A Comprehensive Review and Meta Analysis. Canc Therapy & Oncol Int J. 2022; 20(5):556047. DOI:10.19080/CTOIJ.2022.20.556
29. Hong H, Branham WS, Dial SL, et al. Rat α-Fetoprotein Binding Affinities of a Large Set of Structurally Diverse Chemicals Elucidated the Relationships between Structures and Binding Affinities. Chem Res Toxicol. 2012; 25 (11):2553–2566. doi.org/10.1021/tx3003406.
30. Terentiev AA, Moldogazieva NT, Levtsova OV, et al. Modeling of Three Dimensional Structure of Human Alpha-Fetoprotein Complexed with Diethylstilbestrol: Docking and Molecular Dynamics Simulation Study. J Bioinf Comp Biol. 2012; 10 (2):1241012. doi.org/10.1142/S0219720012410120
31. Laderoute MP. A New Paradigm about HERV-K102 Particle Production and Blocked Release to Explain Cortisol Mediated Immunosenescence and Age-Associated Risk of Chronic Disease. Disc Med. 2015; 20 (112):379–391. PMID: 26760982
32. AlphaFold Protein Structure Database webpage. https://alphafold.ebi.ac.uk/. Reached May 4, 2023.
33. Vallette G, Vranckx R, Martin M.-E, et al. Conformational Changes in Rodent and Human α-Fetoprotein: Influence of Fatty Acids. BBA - Protein Structure and Molecular Enzymology. 1989; 997 (3):302–312. doi.org/10.1016/0167-4838(89)90201-X
34. Uversky VN, Narizhneva NV, Ivanova TV, et al. Rigidity of Human α-Fetoprotein Tertiary Structure Is under Ligand Control. Biochem. 1997; 36 (44):13638–13645. doi.org/10.1021/bi970332p
35. Uversky VN, Narizhneva NV. Effect of Natural Ligands on the Structural Properties and Conformational Stability of Proteins. (Rus.) Biokhim. 1998; 63 (4):420–433. pubmed.ncbi.nlm.nih.gov/9556525
36. Dudich IV, Semenkova LN, Tatulov E, et al. Improved delivery of poorly water-soluble drugs with alphafetoprotein stabilized with metal ions. World Intellectual Property Organization WO2015075296A1, filed November 18, 2014, and issued May 28, 2015. https://patents.google.com/patent/WO2015075296A1/en
37. Permyakov SE, Oberg KA, Cherskaya AM, et al. Human α-Fetoprotein as a Zn2+-Binding Protein. Tight Cation Binding Is Not Accompanied by Global Changes in Protein Structure and Stability. BBA - Molecular Basis of Disease. 2002;1586 (1):1–10. doi.org/10.1016/S0925-4439(01)00079-5
38. Strelchenok O. 2003. Composition for the treatment of immune deficiencies and methods for its preparation and use. US Patent: 6599507, issued July 29, 2003. http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6599507.PN.&OS=PN/6599507&RS=PN/6599507
39. Gaisinskaya P, Vanhelmond T, Mamoneet M. Extreme Alpha Fetoprotein Level and Parathyroid Hormone-Related Peptide Paraneoplastic Syndrome: A Unique Case Report of Hepatocellular Carcinoma. Front Med Case Rep. 2021; 2(6):1-05. DOI: dx.doi.org/10.47746/FMCR.2021.2607
40. Belyaev NN, Bogdanov AYu, Savvulidi PhG, et al. The influence of alpha-fetoprotein on natural suppressor cell activity and Ehrlich carcinoma growth. Korean J. Physiol. Pharmacol. 2008; 12:193-197. doi.org/10.4196/kjpp.2008.12.4.193
41. Griffin P, Hill WA, Rossi F, et al. High anti-tumor activity of a novel alpha-fetoprotein-maytansinoid conjugate targeting alpha-fetoprotein receptors in colorectal cancer xenograft model. Cancer Cell Int. 2023; 23(1):60. doi: 10.1186/s12935-023-02910-0]. pubmed.ncbi.nlm.nih.gov/37016369
42. Sangro B, Sarobe P, Hervás-Stubbs S. et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18:525–543. doi.org/10.1038/s41575-021-00438-0
43. Bai DS, Zhang C, Chen P, et al. The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma. Sci Rep. 2017; 7(1):12870. doi: 10.1038/s41598-017-12834-1
44. Lu Y, Zhu M, Li W, et al. Alpha Fetoprotein Plays a Critical Role in Promoting Metastasis of Hepatocellular Carcinoma Cells. J Cell Mol Med. 2016; 20 (3):549–558. doi.org/10.1111/jcmm.12745
45. Patel A, Espat NJ, Somasundar P. Fibrolamellar Carcinoma: Novel Insights into a Rare Subtype. Ann Surg Oncol. 2020; 27:1733–1734. doi.org/10.1245/s10434-020-08253-8
46. Laderoute MP, Pilarski LM. The Inhibition of Apoptosis by Alpha-Fetoprotein (AFP) and the Role of AFP Receptors in Anti-Cellular Senescence. Anticancer Res. 1994; 14 (6B):2429–2438. PMID: 7532927
47. Semenkova LN, Dudich EI, Dudich IV. Induction of Apoptosis in Human Hepatoma Cells by Alpha-Fetoprotein. Tumor Biol. 1997; 18 (5):261–273. doi.org/10.1159/000218039
48. Jang S, Choi GH, Chang W, et al. Elevated alpha-fetoprotein in asymptomatic adults: Clinical features, outcome, and association with body composition. PLoS ONE. 2022; 17(7):e0271407. doi.org/10.1371/journal.pone.0271407
49. Daily Mail. My Life Was Saved by My Unborn Baby. Mail Online. 2013; December 3, 2013. https://www.dailymail.co.uk/health/article-2517436/My-unborn-baby-saved-life-Mother-didnt-know-expecting-discovers-pregnancy-hormones-destroyed-cancerous-tumour.html
50. Reshetnikov SS. The method of obtaining the drug alpha-fetoprotein. (Rus.). 1998; Patent RU2123009C1, filed April 2, 1998, and issued December 10, 1998. Russia. patents.google.com/patent/RU2123009C1/ru
51. Zamorina SA, Shardina KY, Timganova VP, et al. Effect of Alpha-Fetoprotein on Differentiation of Myeloid Supressor Cells. Dokl Biochem Biophys. 2021; 501(1):434-437. doi: 10.1134/S1607672921060077
52. Zamorina SA, Timganova VP, Bochkova MS, et al. α-Fetoprotein Influence on the Conversion of Naïve T-Helpers into Memory T-Cell Effector Subpopulations. 2018, Dokl Akad Nauk. 2018; 482: 210–213. doi.org/10.1134/S0012496618050113
53. Bimbetov BR, Sadikov KB, and Reshetnikov SS. Method for treating viral hepatitis C. (Rus.) 2005; Kazach Patent Database, KZ15922, issued 2005. kzpatents.com/0-pp15922-sposob-lecheniya-hronicheskogo-virusnogo-gepatita-s.html
54. Abdulsamad B, Afifi M, Awaad AK, et al. Effect of Direct Acting Antivirals (DAAs) on Myeloid-Derived Suppressor Cells Population in Egyptian Chronic Hepatitis C Virus Patients: A Potential Immunomodulatory Role of DAAs. Viral Immunol. 2022; doi.org/10.1089/vim.2022.0170
55. Bimbetov BR. Method for treating viral hepatitis А (Rus). 2005; 15.05.2006 PP 17334 Kazach Patent Database, KZ 16154, issued 2005. kzpatents.com/0-pp17334-sposob-lecheniya-virusnogo-gepatita-a.html
56. Rodionov SJ, Chereshnev VA, Egorov OB, et al. Meducation composition and method of its obtaining for treatment of chronic viral hepatitis B or C and AIDS. RU 2 440 133 C2. Published January 20, 2012. patenton.ru/patent/RU2440133C2/en
57. Sadikov KB, Irismetov MP, Аbuova GN, et al. Method for treating chronic viral hepatitis D. (Rus.) 2005; Kazach Patent Database, KZ15922, issued September 15, 2005. kzpatents.com/0-pp16154-sposob-lecheniya-hronicheskogo-virusnogo-gepatita-d.html
58. Chereshnev VA, Rodionov SIu, Vasil'ev NV, et al. Alpha-fetoprotein immunotherapy as a stage of combined treatment of cancer patients. Vopr Onkol. 2005; 51(1):86-92. Russian. PMID: 15909814
59. Vujanovic L, Stahl EC, Pardee AD, et al. Tumor-Derived α-Fetoprotein Directly Drives Human Natural Killer-Cell Activation and Subsequent Cell Death. Cancer Immunol Res. 2017; 5(6):493-502. doi: 10.1158/2326-6066.CIR-16-0216
60. ACT website. Reached on May 4, 2023.
61. Dudich E. MM-093, a recombinant human alpha-fetoprotein for the potential treatment of rheumatoid arthritis and other autoimmune diseases. Curr Opin Mol Ther. 2007; 9(6):603-610. PMID: 18041671
62. Xu D, Li C, Xu Y, et al. Myeloid-derived suppressor cell: A crucial player in autoimmune diseases. Front. Immunol. 2022; 13:1021612. doi: 10.3389/fimmu.2022.1021612
63. Pollard LC, Murray J, Moody M, et al. A Randomised, Double-Blind, Placebo-Controlled Trial of a Recombinant Version of Human Alpha-Fetoprotein (MM-093) in Patients with Active Rheumatoid Arthritis. Ann Rheum Dis. 2007; 66 (5):687–89. doi.org/10.1136/ard.2006.059436
64. Kawase Y, Ohe M, Shida H, et al. Methotrexate-induced myelodysplasia mimicking myelodysplastic syndrome. Blood Res. 2018; 53(4):268. doi: 10.5045/br.2018.53.4.268.
65. Park MJ, Lee SH, Kim EK. et al. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice. Sci Rep. 2018; 8, 3753. doi.org/10.1038/s41598-018-21856-2
66. Rajabinejad M, Salari F, Karaji AG, et al. The Role of Myeloid-Derived Suppressor Cells in the Pathogenesis of Rheumatoid Arthritis; Anti- or pro-Inflammatory Cells? Art Cells Nanomed Biotech. 2019; 47 (1):4149–4158. doi.org/10.1080/21691401.2019.1687504
67. Aussel C, Fehlmann M. Effect of alpha-fetoprotein and indomethacin on arachidonic acid metabolism in P388D1 macrophages: role of leukotrienes. Prostagl Leukot Med. 1987; 28(3):325-336. doi: 10.1016/0262-1746(87)90121-1
68. Spector TD, Da Silva JA. Pregnancy and rheumatoid arthritis: an overview. Am. J. Reprod. Immunol. 1992; 28(3–4):222–225. doi: 10.1111/j.1600-0897.1992.tb00797.x
69. Zhao Y, Shen X-F, Cao K, et al. Dexamethasone-Induced Myeloid-Derived Suppressor Cells Prolong Allo Cardiac Graft Survival through INOS- and Glucocorticoid Receptor-Dependent Mechanism. Front Immunol. 2018; 9:282. doi.org/10.3389/fimmu.2018.00282
70. Okano S, Abu-Elmagd K, Kish DD, et al. Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients. Am J Transplant. 2018; 18(10):2544-2558. doi: 10.1111/ajt.14718
71. Zhang K, Bai X, Li R, et al. Endogenous glucocorticoids promote the expansion of myeloid-derived suppressor cells in a murine model of trauma. Int J Mol Med. 2012; 30(2):277-282. doi: 10.3892/ijmm.2012.1014
72. Budhwar S, Verma P, Verma R, et al. The Yin and Yang of Myeloid Derived Suppressor Cells. Front Immunol. 2018; 9:2776. doi.org/10.3389/fimmu.2018.02776
73. Bline KE, Muszynski JA, Guess AJ, et al. Novel Identification of Myeloid-Derived Suppressor Cells in Children With Septic Shock. Pediatr Crit Care Med. 2022; 23(12):e555-e563. doi: 10.1097/PCC.0000000000003071
74. Perfilyeva YV, Ostapchuk YO, Tleulieva R, et al. Myeloid-derived suppressor cells in COVID-19: A review. Clin Immunol. 2022; 238:109024. doi: 10.1016/j.clim.2022.109024
75. Grassi G, Notari S, Gili S, et al. Myeloid-Derived Suppressor Cells in COVID-19: The Paradox of Good. Front. Immunol. 2022; 13:842949. doi: 10.3389/fimmu.2022.842949
76. Desreumaux P, Rousseaux C, and Dubuquoy C. P1280 - Anti-Inflammatory Effect of Recombinant Human Alpha-Fetoprotein (RhAFP) in the Model of TNBS-Induced Colitis. In: Orlando, FL, USA: American College of Gastroenterology. 2017. www.eventscribe.com/2017/wcogacg2017/ajaxcalls/
PosterInfo.asp?efp=S1lVTUxLQVozODMy&PosterID=116509&rnd=0.7294109
77. Linson EA, Hanauer SB. More Than a Tumor Marker. A Potential Role for Alpha-Feto Protein in Inflammatory Bowel Disease. Inflam Bowel Dis. 2019; 25 (7):1271–1276. doi.org/10.1093/ibd/izy394
78. Blumberg RS, Pyzik M, Gandhi A, et al. Blockade of alphafetoprotein (AFP) interactions with beta2-microglobulin associated molecules. United States US20190201496A1, filed September 14, 2017, and issued July 4, 2019, patents.google.com/patent/US20190201496A1/en?oq=US+20190201496
79. Pyzik M, Rath T, Lencer WI, et al. FcRn: The Architect Behind the Immune and Nonimmune Functions of IgG and Albumin. J Immunol (Baltimore, Md.: 1950). 2015; 194 (10): 4595–4603. doi.org/10.4049/jimmunol.1403014
80. Pyzik M, Sand KMK, Hubbard JJ, et al. The Neonatal Fc Receptor (FcRn): A Misnomer? Front Immunol. 2019; 10:1540. doi.org/10.3389/fimmu.2019.01540
81. Severin SE, Kulakov VN, Moskaleva EY, et al. The distribution of iodine-125 labeled alpha-fetoprotein in the animal organism and its accumulation in the tumor. (Rus.) Vest Ros Akad Med Nauk. 2012; 4:11–15. europepmc.org/article/MED/22834322
82. Moskaleva EYu, Posypanova G, Shmyrev I, et al. Alpha-Fetoprotein-Mediated Targeting - A New Strategy to Overcome Multidrug Resistance of Tumour Cells in Vitro. Cell Biol Intl. 1998; 21:793–799. doi.org/10.1006/cbir.1998.0201
83. Severin SE, Posypanova GA, Sotnichenko AI, et al. Antitumor activity of a covalent conjugate of the endiene antibiotic esperamicin A1 with human alpha-fetoprotein. (Rus.) Dokl Akad Nauk. 1999; 366 (4):561–564. pubmed.ncbi.nlm.nih.gov/10439917
84. Zamorina SA, Rayev MB, Cherechnev VA. The use of alpha-fetoprotein in immunopharmacology – history of the subject. Bull Perm Univ. Biol. 2020; (2):145–153. Doi: 10.17072/1994-9952-2020-2-145-153
85. Lin B, Dong X, Wang Q, et al. AFP-Inhibiting fragments for drug delivery: the promise and challenges of targeting therapeutics to cancers. Front. Cell Dev. Biol. 2021; 9, 635476. doi.org/10.3389/fcell.2021.635476
86. Gulevskyy OK, Akhatova YuS. Current Concept of the Structural and Functional Properties of Alpha-Fetoprotein and Possibilities of its Clinical Application. Biotech. Acta. 2021; 14(1):25-37. doi.org/10.15407/biotech14.01.025
87. Sokol MB, Yabbarov NG, Mollaeva MR, et al. Alpha-fetoprotein mediated targeting of polymeric nanoparticles to treat solid tumors. Nanomed. 2022; 17(18):1217–1235. doi.org/10.2217/nnm-2022-0097
88. Clappaert EJ, Murgaski A, Van Damme H, et al. Diamonds in the Rough: Harnessing Tumor- Associated Myeloid Cells for Cancer Therapy. Front Immunol. 2018; 9: 2250. doi.org/10.3389/fimmu.2018.02250
89. De Sanctis F, Adamo A, Canè S. et al. Targeting tumour-reprogrammed myeloid cells: the new
battleground in cancer immunotherapy. Semin Immunopathol. 2023; 45:163–186. doi.org/10.1007/s00281-022-00965-1
90. Pak V. Alpha-Fetoprotein Binds Toxins and Can Be Used to Treat Cancer. Med Res Arch. 2022; 10(10). doi:10.18103/mra.v10i10.3236.
91. Ren J, Zeng W, Tian F, et al. Myeloid‐derived Suppressor Cells Depletion May Cause Pregnancy Loss via Upregulating the Cytotoxicity of Decidual Natural Killer Cells. Amer J Repr Immunol. 2019; 81 (4):e13099. doi.org/10.1111/aji.13099
92. Belyaev NN. Myeloid-Derived Suppressor Cells (MDSC) as a Main Tumor Induced Negative Regulators of Cancer Immunity and Possible Ways for Their Elimination. KazNU Bull Biol series. 2014; 1(60):79–83.
93. Belyaev NN, Abdolla N, Perfilyeva YV, et al. Daunorubicin Conjugated with Alpha-Fetoprotein Selectively Eliminates Myeloid-Derived Suppressor Cells (MDSCs) and Inhibits Experimental Tumor Growth. Cancer Immunol Immunother: CII. 2018; 67(1):101–111. doi.org/10.1007/s00262-017-2067-y
94. Wan D, Yang Y, Liu Y, et al. Sequential Depletion of Myeloid-Derived Suppressor Cells and Tumor Cells with a Dual-PH-Sensitive Conjugated Micelle System for Cancer Chemoimmunotherapy. J Contr Rel. 2020; 317:43–56. doi.org/10.1016/j.jconrel.2019.11.011
95. Kumar P, Kumar A, Parveen S, et al. Recent Advances with Treg Depleting Fusion Protein Toxins for Cancer Immunotherapy. Immunother. 2019; 11 (13):1117–1128. doi.org/10.2217/imt-2019-0060
96. Pak VN. The perfect combination of the most powerful cancer immunotherapy with the best targeted chemotherapy. Canc. Ther. Oncol. Int J. 2022; 20(5), 556050. https://juniperpublishers.com/ctoij/CTOIJ.MS.ID.556050.php
97. Govallo VI. Immunology of Pregnancy and Cancer. 1993. Commack, N.Y: Nova Science Publishers.
98. Głowska-Ciemny J, Szymański M, Kuszerska A, et al. The Role of Alpha-Fetoprotein (AFP) in Contemporary Oncology: The Path from a Diagnostic Biomarker to an Anticancer Drug. Int. J. Mol. Sci. 2023; 24(3):2539. doi.org/10.3390/ijms24032539
99. Torres JM, Geuskens M, and Uriel J. Receptor-Mediated Endocytosis and Recycling of Alpha-Fetoprotein in Human B-Lymphoma and T-Leukemia Cells. Int J Can. 1991; 47 (1):110–117. doi.org/10.1002/ijc.2910470120
100. Villacampa MJ, Moro R, Naval J, et al. Alpha-fetoprotein receptors in a human breast cancer cell line. Biochem Biophys Res Commun. 1984; 16; 122(3):1322-1327. doi: 10.1016/0006-291x(84)91236-1
101. Deutsch HF, Tsukada TS, Sasaki T, et al. Cytotoxic Effects of Daunomycin-Fatty Acid Complexes on Rat Hepatoma Cells. Cancer Res. 1983; 43 (6):2668–2672. pubmed.ncbi.nlm.nih.gov/6850584
102. Hirano K, Watanabe Y, Adachi T, et al. Drug-binding properties of human alpha-foetoprotein. Biochem J. 1985; 231(1):189-191. doi: 10.1042/bj2310189
103. Mayer EL. An Oncologist’s Perspective on the Clinical Use of Teratogenic Products. Dana-Farber Cancer Institute, Boston, MA, USA.
www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ DrugSafetyandRiskManagementAdvisoryCommittee/UCM333370.pdf
104. Wang L, Wei L, Zhang S, et al. An Informatics Bridge to Improve the Design and Efficiency of Phase I Clinical Trials for Anticancer Drug Combinations. Can Res Commun. 2022; 2(9):929-936. doi.org/10.1158/2767-9764.CRC-22-0160
105. Sotnichenko AI, Severin SE, Posypanova GA, et al. Water-Soluble 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Complex with Human Alpha-Fetoprotein: Properties, Toxicity in Vivo and Antitumor Activity in Vitro. FEBS Letters. 1999; 450 (1–2):49–51. doi.org/10.1016/s0014-5793(99)00440-8.
106. Azarova IN, Kuchkina AIu, Baram GI, et al. Prediction of peptide retention volumes in the gradient reversed phase HPLC. Bioorg Khim. 2008; 34(2):171-176. Russian. doi: 10.1134/s1068162008020039
107. Pak VN, Pak NA, Reshetnikov SS, et al. 2005. Method of treatment of malignant neoplasms and complex preparation having antineoplastic activity for use in such treatment. United States US6878688B2, filed June 20, 2001, issued April 12, 2005. patents.google.com/patent/US6878688B2/en
108. Santomasso B, Bachier C, Westin J, et al. The Other Side of CAR T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden. ASCO Edu Book. 2019; 39:433–44. doi.org/10.1200/EDBK_238691
109. Sevko A, Michels T, Vrohlings M, et. al. Antitumor Effect of Paclitaxel Is Mediated by Inhibition of Myeloid-Derived Suppressor Cells and Chronic Inflammation in the Spontaneous Melanoma Model. J Immunol (Baltimore, Md.: 1950). 2013; 190 (5):2464–2471. doi.org/10.4049/jimmunol.1202781
110. Kotra LP, Paige CJ, Bello AM, et al. 2016. Drug complexes comprising alpha-fetoprotein. Patent WO/2016/119045A1. patentimages.storage.googleapis.com/0c/a7/ee/1fd56e9fbcb392/WO2016119045A1.pdf
111. Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-derived suppressor cells as a therapeutic target for cancer. Cells. 2020; 9(3):561. doi.org/10.3390/cells9030561
112. Anger N, Rossowska J. Myeloid-derived suppressor cells as a target for anticancer therapy. Post Hig Med Dośw. 2018; 72:1179–1198. doi.org/10.5604/01.3001.0012.8267
113. Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010; 70:3052–3061. doi: 10.1158/0008-5472.CAN-09-3690
114. Alizadeh D, Trad M, Hanke NT, et al. Doxorubicin Eliminates Myeloid-Derived Suppressor Cells and Enhances the Efficacy of Adoptive T-Cell Transfer in Breast Cancer. Cancer Res. 2014; 74 (1):104–18. doi.org/10.1158/0008-5472.CAN-13-1545
115. Dudich E, Semenkova L, Dudich I, et al. Recombinant Alpha-fetoprotein And Compositions Thereof. US Patent: 20110159112 A1, issued 2011-06-30.
116. Pak V. Oncoshuttle Canadian Trademark TMA951175. trademark.trademarkia.com/ca/oncoshuttle-1738151.htm
117. McCrudden MTC, Singh TRR, Migalska K, et al. Strategies for Enhanced Peptide and Protein Delivery. Ther Deliv. 2013; 4 (5):593–614. doi.org/10.4155/tde.13.31
118. Starikov VV, Rodionov SYu. 2000. Method of alpha-fetoprotein-containing tablet making. (Rus.) Ratent of Russia RU2154468C1, filed 1999, and issued 2000. yandex.ru/patents/doc/RU2154468C1_20000820
119. Thornthwaite JT, Roland LH, England SR, et al. Anticancer Effects of Curcumin, Artemisinin, Genistein, and Resveratrol, and Vitamin C: Free Versus Liposomal Forms. Adv Biol Chem. 2017; 7 (1):720–726. doi.org/10.4236/abc.2017.71002
120. Arshad NM, In LLA, Soh TL, et al. Recombinant Human Alpha Fetoprotein Synergistically Potentiates the Anti-Cancer Effects of 1’-S-1’-Acetoxychavicol Acetate When Used as a Complex against Human Tumours Harbouring AFP-Receptors. Oncotarget. 2015; 6(18):16151–16167. doi.org/10.18632/oncotarget.3951
121. Pak VN. In: Alpha-fetoprotein and Its Receptor in Fixing the Cancer Brakes. Cambridge Scholars Publishing, Tyne, England. 2021; 209p. ISBN: 1-5275-6716-8
122. Cassandri M, Smirnov A, Novelli F, et al. Zinc-finger proteins in health and disease. Cell Death Discov. 2017; 3:17071. doi.org/10.1038/cddiscovery.2017.71
123. Putt KS, Chen GW, Pearson JM, et al. Small-Molecule Activation of Procaspase-3 to Caspase-3 as a Personalized Anticancer Strategy. Nat Chem Biol. 2006; 2(10):543–50. doi.org/10.1038/nchembio814
124. Cheng G, Zhang Q, Pan J, et al. Targeting Lonidamine to Mitochondria Mitigates Lung Tumorigenesis and Brain Metastasis. Nat Commun. 2019; 10(1):2205. doi.org/10.1038/s41467-019-10042-1
125. Fang N, and Casida JE. Anticancer Action of Cubé Insecticide: Correlation for Rotenoid Constituents between Inhibition of NADH: Ubiquinone Oxidoreductase and Induced Ornithine Decarboxylase Activities. PNAS. 1998; 95(7):3380–3384. doi.org/10.1073/pnas.95.7.3380
126. Heinz S, Freyberger A, Lawrenz B, et al. Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation. Sci Rep. 2017; 7:45465. doi.org/10.1038/srep45465
127. Jaskulska A, Janecka AE, Gach-Janczak K. Thapsigargin-From Traditional Medicine to Anticancer Drug. Int J Mol Sci. 2020; 22(1):4. doi: 10.3390/ijms22010004
128. Goulding LV, Yang J, Jiang Z, et al. Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication. Viruses. 2020; 12(10):1093. doi: 10.3390/v12101093
129. Popat A, Shear NH, Malkiewicz I, et al. The toxicity of Callilepis laureola, a South African traditional herbal medicine. Clin Biochem. 2001; 34(3):229-236. doi: 10.1016/s0009-9120(01)00219-3
130. Pak VN, Molchanov O, Vincent M. Treatment of Metastatic Colorectal Cancer with Aimpila, a Glycoside/Alpha-Fetoprotein Complex. J Clin Oncol. 2007; 25(18_suppl):3589–3589. doi.org/10.1200/jco.2007.25.18_suppl.3589
131. Pak V. Compositions of alpha-fetoprotein and inducers of apoptosis for the treatment of cancer. WO patent 2007056852A1. 2006. patents.google.com/patent/WO2007056852A1/en
132. Shevkun N, Karapetian R, and Leonov S. Investigation of Bioavailability of PAFP after Oral Administration of PAFP and Complex PAFP-Rotenone in Mice. ChemDiv report ID: CDRI-PAFP_PK_M-2011-05_v2. Moscow, Russia: Chem.Div. Inc. 2011. (Unpublished).
133. Tumino N, Besi F, Martini S, et al. Polymorphonuclear Myeloid-Derived Suppressor Cells Are Abundant in Peripheral Blood of Cancer Patients and Suppress Natural Killer Cell Anti-Tumor Activity. Front. Immunol. 2022; 12:803014. doi: 10.3389/fimmu.2021.803014.
134. Naz Z, Usman S, Saleem K, et al. Alpha-Fetoprotein: A Fabulous Biomarker in Hepatocellular, Gastric and Rectal Cancer Diagnosis. Biomed Res. 2018; 29 (12). doi.org/10.4066/biomedicalresearch.29-17-1550
135. Tsuboi S, Taketa K, Nouso K, et al. High Level of Expression of Alpha-Fetoprotein Receptor in Gastric Cancers. Tumour Biol. 2006; 27(6):283–88. doi.org/10.1159/000096071
136. Chun H, and Kwon SJ. Clinicopathological Characteristics of Alpha-Fetoprotein-Producing Gastric Cancer. J Gastr Can. 2011; 11(1):23. doi.org/10.5230/jgc.2011.11.1.23
137. Hameedat F, Pizarroso NA, Teixeira N, et al. Functionalized FcRn-targeted nanosystems for oral drug delivery: A new approach to colorectal cancer treatment. Eur J Pharm Sci. 2022; 176:106259. doi.org/10.1016/j.ejps.2022.106259
138. Anel A, Calvo M, Naval J, et al. Interaction of Rat α-Fetoprotein and Albumin with Polyunsaturated and Other Fatty Acids: Determination of Apparent Association Constants. FEBS Letters. 1989; 250 (1):22–24. doi.org/10.1016/0014-5793(89)80676-3
139. Kumar V, Patel S, Tcyganov E, et al. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016; 37(3):208–220. doi.org/10.1016/j.it.2016.01.004
140. Zhu X, Meng G, Dickinson BL, et al. MHC Class I-Related Neonatal Fc Receptor for IgG Is Functionally Expressed in Monocytes, Intestinal Macrophages, and Dendritic Cells. J Immunol. 2001; 166(5):3266–3276. doi.org/10.4049/jimmunol.166.5.3266
141. Latvala S, Jacobsen B, Otteneder MB, et al. Distribution of FcRn Across Species and Tissues. J Hist & Cytochem. 2017; 65 (6):321–333. doi.org/10.1369/0022155417705095
142. Thomas J, Torok MA, Agrawal K, et al. The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer. Int. J. Mol. Sci. 2022; 23:7066. doi.org/10.3390/ijms23137066
143. Pak VN. Alpha-Fetoprotein Binds Toxins and Can Be Used to Treat Cancer. Med Res Arch. 2022; [S.l.], 10(10). doi.org/10.18103/mra.v10i10.3236
144. Pak VN. A Cancer Prevention and Treatment Opportunity. Glob J Med Res: F Dis. 2023; 23(2):7-15. globaljournals.org/GJMR_Volume23/2-A-Cancer-Prevention-and-Treatment-Opportunity.pdf
145. Su Y-T, Chen J-S, Lan K-C, et al. Direct Effects of Mifepristone on Mice Embryogenesis: An In Vitro Evaluation by Single-Embryo RNA Sequencing Analysis. Biomedicines. 2023; 11(3):907. https://doi.org/10.3390/biomedicines11030907
146. Cao L, Tang Y, Niu X, et al. Mifepristone regulates macrophage-mediated natural killer cells function in decidua. Repr Biol. 2021; 21(3):100541. doi.org/10.1016/j.repbio.2021.100541
147. Jewett A, Kos J, Kaur K, et al. Natural Killer Cells: Diverse Functions in Tumor Immunity and Defects in Pre-neoplastic and Neoplastic Stages of Tumorigenesis. Mol Ther Oncolytics. 2019; 16:41-52. doi:10.1016/j.omto.2019.11.002
148. Yousefnia S. A comprehensive review on miR-153: Mechanistic and controversial roles of miR-153 in tumorigenicity of cancer cells. Front. Oncol. 2022; 12:985897. doi: 10.3389/fonc.2022.985897
149. Llaguno-Munive M, Vazquez-Lopez MI, Jurado R, et al. Mifepristone Repurposing in Treatment of High-Grade Gliomas. Front Oncol. 2021; 11:606907. doi: 10.3389/fonc.2021.606907.
150. Check JH, Check D, and Poretta T. Mifepristone Extends Both Length and Quality of Life in a Patient with Advanced Non-small Cell Lung Cancer that Has Progressed Despite Chemotherapy and a Check-point Inhibitor. Anticancer Res. 2019; 39:1923-1926. doi:10.21873/anticanres.13301
151. Elía A, Saldain L, Vanzulli SI, et al. Beneficial effects of mifepristone treatment in breast cancer patients selected by the progesterone receptor isoform ratio: Results from the MIPRA trial. Clin Cancer Res. 2023; 29(5):866–877. doi.org/10.1158/1078-0432.CCR-22-2060
152. Ponandai-Srinivasan S, Lalitkumar PG, Garcia L, et al, Gemzell-Danielsson K, et al. Mifepristone mediates anti-proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA1-/2- carriers. Acta Obstet Gynecol Scand. 2019; 98(2):250–61. doi: 10.1111/aogs.13485
153. Alvarez PB, Laskaris A, Goyeneche AA, et al. Anticancer effects of mifepristone on human uveal melanoma cells. Cancer Cell Int. 2021; 21, 607. doi.org/10.1186/s12935-021-02306-y
154. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2013-02151&r=1