Исследование противоопухолевых эффектов гидролизата плаценты человека на культурах клеток PC-3, OAW-42, BT-474

Громова О.А., Филимонова М.В., Торшин И.Ю., Фролова Д.Е. Исследование противоопухолевых эффектов гидролизата плаценты человека на культурах клеток PC-3, OAW-42, BT-474. Терапевтический архив. 2024;96(3):266–272. DOI: 10.26442/00403660.2024.03.202624

© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.

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Gromova OA, Filimonova MV, Torshin IYu, Frolova DЕ. Study of antitumor effects of human placenta hydrolysate on PC-3, OAW-42, BT-474 cell cultures. Terapevticheskii Arkhiv (Ter. Arkh.). 2024;96(3):266–272.
DOI: 10.26442/00403660.2024.03.202624

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Аннотация

Цель. Исследовать противоопухолевые эффекты пептидов гидролизата плаценты человека (ГПЧ) на трех гормонозависимых линиях клеток человека: аденокарциномы простаты, карциномы молочной железы и рака яичника посредством метаболического анализа культур клеток.
Материалы и методы. Проведены оценки эффектов ГПЧ на опухолевые и контрольные линии опухолевых клеток. Этапы исследования: (А) de novo секвенирование пептидов методом коллизионно-индуцированной диссоциации масс-спектрометрии; (Б) выявление пептидов с противоопухолевыми свойствами; (В) экспертный анализ полученных списков пептидов.
Результаты. Показаны дозозависимые цитотоксические эффекты ГПЧ на трех опухолевых клеточных линиях: PC-3 (аденокарциномы простаты человека), OAW-42 (рака яичника человека), BT-474 (карциномы молочной железы человека) и получены значения констант IC₅₀(1,3–2,8 мг/мл). Представлены результаты анализа пептидной фракции ГПЧ, указывающие на более чем 70 пептидов с противоопухолевыми свойствами в составе данного ГПЧ (ингибиторы киназ: митоген-активируемых протеинкиназ, киназы ингибитора нуклеарного фактора каппа-би, AKT серин/треонинкиназы 1, Z-протеинкиназы C, киназы 4, ассоциированной с рецептором интерлейкина-1, и циклинзависимой киназы 1).
Заключение. Результаты исследования позволяют утверждать не только онкобезопасность применения ГПЧ при терапии, но и слабые противоопухолевые эффекты данного ГПЧ, проявляющиеся при высоких концентрациях.

Ключевые слова: молекулярная фармакология, плацентарная терапия, постгеномная медицина, биоинформатика, онкобезопасность препаратов

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Aim. To investigate the antitumor effects of human placenta hydrolysate (HPH) peptides on three hormone-dependent human cell lines: prostate adenocarcinoma, breast carcinoma, and ovarian cancer by metabolic analysis of cell cultures.
Materials and methods. The effect of HPH on tumor and control tumor cell lines was evaluated. Study stages: (A) de novo peptide sequencing by collision-induced dissociation mass spectrometry; (B) detection of peptides with anti-tumor properties; (C) expert analysis of the obtained lists of peptides.
Results. Dose-dependent cytotoxic effects of HPH on three tumor cell lines are shown: PC-3 (human prostate adenocarcinomas), OAW-42 (human ovarian cancer), BT-474 (human breast carcinomas), and IC₅₀ constants (1.3–2.8 mg/ml) were obtained. The analysis of the HPH peptide fraction showed more than 70 peptides with antitumor properties in the composition of this HPH, including kinase inhibitors: mitogen-activated protein kinases, kappa-bi nuclear factor inhibitor kinase, AKT serine/threonine kinase 1, protein kinase C zeta, interleukin-1 receptor-associated kinase 4 and cyclin-dependent kinase 1.
Conclusion. The results of the study indicate not only the oncological safety of the HPH used in therapy but also the mild antitumor effects of this HPH at high concentrations.

Keywords: molecular pharmacology, placental therapy, postgenomic medicine, bioinformatics, oncological safety of drugs

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Список литературы

1. Громова О.А., Торшин И.Ю., Чучалин А.Г., Максимов В.А. Гидролизаты плаценты человека: от В.П. Филатова до наших дней. Терапевтический архив. 2022;94(3):434-41 [Gromova OA, Torshin IYu, Chuchalin AG, Maksimov V.A. Human placenta hydrolysates: From V.P. Filatov to the present day. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(3):434-41 (in Russian)]. DOI:10.26442/00403660.2022.03.201408
2. Громова О. А., Торшин И. Ю., Тихонова О. В., Згода В. Г. Гепатопротекторные пептиды препарата Лаеннек. Экспериментальная и клиническая гастроэнтерология. 2022;203(7):21-30 [Gromova OA, Torshin IYu, Tikhonova OV, Zgoda VG. Hepatoprotective peptides of the drug Laennec. Experimental and Clinical Gastroenterology. 2022;203(7):21-30 (in Russian)]. DOI:10.31146/1682-8658-ecg-203-7-21-30
3. Громова О.А., Торшин И.Ю., Громов А.Н., Тихонова О.В. Нефропротекторные пептиды препарата Лаеннек® в контексте фармакотерапии нефрогепатометаболических нарушений. Фармакоэкономика. Современная фармакоэкономика и фармакоэпидемиология. 2023;16(4):570-86 [Gromova OA, Torshin IYu, Gromov АN, Tikhonova OV. Nephroprotective peptides of Laennec® in the context of pharmacotherapy for nephro-hepato-metabolic disorders. Farmakoekonomika. Modern Pharmacoeconomics and Pharmacoepidemiology. 2023;16(4):570-86 (in Russian)]. DOI:10.17749/2070-4909/farmakoekonomika.2023.215
4. Ghoneum M, El-Gerbed MSA. Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses. Cancer Chemother Pharmacol. 2021;88(6):961-71. DOI:10.1007/s00280-021-04349-4
5. Mahran HA, Khedr YI, Gawaan YM, El-Gerbed MSA. Possible ameliorative effect of human placental extract on methotrexate-induced nephrotoxicity in albino rats. JoBAZ. 2022:83:39. DOI:10.1186/s41936-022-00302-w
6. Nurieva EV, Trofimova TP, Alexeev AA, et al. Synthesis and antihypotensive properties of 2-amino-2-thiazoline analogues with enhanced lipophilicity. Mendeleev Communications. 2018;28(4):390-2. DOI:10.1016/j.mencom.2018.07.016
7. Кейтс М. Техника липидологии. М.: Мир, 1975 [Keits M. Tekhnika lipidologii. Moscow: Mir, 1975 (in Russian)].
8. Дарбре А. Практическая химия белка. М.: Мир, 1989 [Darbre A. Prakticheskaia khimiia belka. Moscow: Mir, 1989 (in Russian)].
9. Torshin IY, Rudakov KV. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 1: Factorization approach. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2017;27(1):16-28. DOI:10.1134/S1054661817010151
10. Torshin IYu, Rudakov KV. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 2: Metric approach within the framework of the theory of classification of feature values. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2017;27(2):184-99. DOI:10.1134/S1054661817020110
11. Torshin IY. Optimal dictionaries of the final information on the basis of the solvability criterion and their applications in bioinformatics. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2013;23(2):319-27. DOI:10.1134/S1054661813020156
12. Torshin IYu, Rudakov KV. On the theoretical basis of the metric analysis of poorly formalized problems of recognition and classification. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2015;25(4):577-87. DOI:10.1134/S1054661815040252
13. Torshin IYu, Rudakov KV. On metric spaces arising during formalization of problems of recognition and classification. Part 2: Density properties. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2016;26(3):483-96. DOI:10.1134/S1054661816030202
14. Torshin IY, Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2014;24(1):11-23. DOI:10.1134/S1054661814010209
15. Torshin IYu, Rudakov KV. On the procedures of generation of numerical features over partitions of sets of objects in the problem of predicting numerical target variables. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2019;29(4):654-67. DOI:10.1134/S1054661819040175
16. Torshin IYu. Sensing the change from molecular genetics to personalized medicine. Ed. OA Gromova. New York: Nova Biomedical Books, 2009.
17. Шадрин В.С., Кожин П.М., Шошина О.О., и др. Теломеризованные фибробласты как потенциальный объект для 3D-моделирования патологических гипертрофических рубцов in vitro. Вестник РГМУ. 2020;(5):82-90 [Shadrin VS, Kozhin PM, Shoshina OO, et al. Telomerized fibroblasts as a candidate 3D in vitro model of pathological hypertrophic scars. Bulletin of RSMU. 2020;(5):82-90 (in Russian)]. DOI: 10.24075/vrgmu.2020.057
18. Burkhard K, Shapiro P. Use of inhibitors in the study of MAP kinases. Methods Mol Biol. 2010;661:107-22. DOI:10.1007/978-1-60761-795-2_6
19. Sasaki T, Maier B, Koclega KD, et al. Phosphorylation regulates SIRT1 function. PLoS One. 2008;3(12):e4020. DOI:10.1371/journal.pone.0004020
20. Nasrin N, Kaushik VK, Fortier E, et al. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One. 2009;4(12):e8414. DOI:10.1371/journal.pone.0008414
21. Pan Y, Wang Y, Xu J, et al. TG and VLDL cholesterol activate NLRP1 inflammasome by Nuclear Factor-κB in endothelial cells. Int J Cardiol. 2017;234:103. DOI:10.1016/j.ijcard.2016.12.156
22. Nabel GJ, Verma IM. Proposed NF-kappa B/I kappa B family nomenclature. Genes Dev. 1993;7(11):2063. DOI:10.1101/gad.7.11.2063
23. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986;46(5):705-16. DOI:10.1016/0092-8674(86)90346-6
24. Llona-Minguez S, Baiget J, Mackay SP. Small-molecule inhibitors of IkappaB kinase (IKK) and IKK-related kinases. Pharm Pat Anal. 2013;2(4):481-98. DOI:10.4155/ppa.13.31
25. Carter RS, Pennington KN, Ungurait BJ, Ballard DW. In vivo identification of inducible phosphoacceptors in the IKKgamma/NEMO subunit of human IkappaB kinase. J Biol Chem. 2003;278(22):19642-8. DOI:10.1074/jbc.M301705200
26. Bian Y, Song C, Cheng K, et al. An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014;96:253-62. DOI:10.1016/j.jprot.2013.11.014
27. Fu X, Xu M, Song Y, et al. Enhanced interaction between SEC2 mutant and TCR Vβ induces MHC II-independent activation of T cells via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways. J Biol Chem. 2018;293(51):19771-84. DOI:10.1074/jbc.RA118.003668
28. Yamamoto T, Tsutsumi N, Tochio H, et al. Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Mol Immunol. 2014;58(1):66-76. DOI:10.1016/J.MOLIMM.2013.11.008
29. George J, Motshwene PG, Wang H, et al. Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly.
J Biol Chem. 2011;286(2):1341-53. DOI:10.1074/jbc.M110.159996
30. Balakrishnan A, Vyas A, Deshpande K, Vyas D. Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer. World J Gastroenterol. 2016;22(7):2159-64. DOI:10.3748/wjg.v22.i7.2159
31. Daub H, Olsen JV, Bairlein M, et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008;31(3):438-48. DOI:10.1016/j.molcel.2008.07.007
32. Zhou H, Di Palma S, Preisinger C, et al. Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013;12(1):260-71. DOI:10.1021/pr300630k

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1. Gromova OA, Torshin IYu, Chuchalin AG, Maksimov V.A. Human placenta hydrolysates: From V.P. Filatov to the present day. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(3):434-41 (in Russian). DOI:10.26442/00403660.2022.03.201408
2. Gromova OA, Torshin IYu, Tikhonova OV, Zgoda VG. Hepatoprotective peptides of the drug Laennec. Experimental and Clinical Gastroenterology. 2022;203(7):21-30 (in Russian). DOI:10.31146/1682-8658-ecg-203-7-21-30
3. Gromova OA, Torshin IYu, Gromov АN, Tikhonova OV. Nephroprotective peptides of Laennec® in the context of pharmacotherapy for nephro-hepato-metabolic disorders. Farmakoekonomika. Modern Pharmacoeconomics and Pharmacoepidemiology. 2023;16(4):570-86 (in Russian). DOI:10.17749/2070-4909/farmakoekonomika.2023.215
4. Ghoneum M, El-Gerbed MSA. Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses. Cancer Chemother Pharmacol. 2021;88(6):961-71. DOI:10.1007/s00280-021-04349-4
5. Mahran HA, Khedr YI, Gawaan YM, El-Gerbed MSA. Possible ameliorative effect of human placental extract on methotrexate-induced nephrotoxicity in albino rats. JoBAZ. 2022:83:39. DOI:10.1186/s41936-022-00302-w
6. Nurieva EV, Trofimova TP, Alexeev AA, et al. Synthesis and antihypotensive properties of 2-amino-2-thiazoline analogues with enhanced lipophilicity. Mendeleev Communications. 2018;28(4):390-2. DOI:10.1016/j.mencom.2018.07.016
7. Keits M. Tekhnika lipidologii. Moscow: Mir, 1975 (in Russian).
8. Darbre A. Prakticheskaia khimiia belka. Moscow: Mir, 1989 (in Russian).
9. Torshin IY, Rudakov KV. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 1: Factorization approach. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2017;27(1):16-28. DOI:10.1134/S1054661817010151
10. Torshin IYu, Rudakov KV. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 2: Metric approach within the framework of the theory of classification of feature values. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2017;27(2):184-99. DOI:10.1134/S1054661817020110
11. Torshin IY. Optimal dictionaries of the final information on the basis of the solvability criterion and their applications in bioinformatics. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2013;23(2):319-27. DOI:10.1134/S1054661813020156
12. Torshin IYu, Rudakov KV. On the theoretical basis of the metric analysis of poorly formalized problems of recognition and classification. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2015;25(4):577-87. DOI:10.1134/S1054661815040252
13. Torshin IYu, Rudakov KV. On metric spaces arising during formalization of problems of recognition and classification. Part 2: Density properties. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2016;26(3):483-96. DOI:10.1134/S1054661816030202
14. Torshin IY, Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2014;24(1):11-23. DOI:10.1134/S1054661814010209
15. Torshin IYu, Rudakov KV. On the procedures of generation of numerical features over partitions of sets of objects in the problem of predicting numerical target variables. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2019;29(4):654-67. DOI:10.1134/S1054661819040175
16. Torshin IYu. Sensing the change from molecular genetics to personalized medicine. Ed. OA Gromova. New York: Nova Biomedical Books, 2009.
17. Shadrin VS, Kozhin PM, Shoshina OO, et al. Telomerized fibroblasts as a candidate 3D in vitro model of pathological hypertrophic scars. Bulletin of RSMU. 2020;(5):82-90 (in Russian). DOI: 10.24075/vrgmu.2020.057
18. Burkhard K, Shapiro P. Use of inhibitors in the study of MAP kinases. Methods Mol Biol. 2010;661:107-22. DOI:10.1007/978-1-60761-795-2_6
19. Sasaki T, Maier B, Koclega KD, et al. Phosphorylation regulates SIRT1 function. PLoS One. 2008;3(12):e4020. DOI:10.1371/journal.pone.0004020
20. Nasrin N, Kaushik VK, Fortier E, et al. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One. 2009;4(12):e8414. DOI:10.1371/journal.pone.0008414
21. Pan Y, Wang Y, Xu J, et al. TG and VLDL cholesterol activate NLRP1 inflammasome by Nuclear Factor-κB in endothelial cells. Int J Cardiol. 2017;234:103. DOI:10.1016/j.ijcard.2016.12.156
22. Nabel GJ, Verma IM. Proposed NF-kappa B/I kappa B family nomenclature. Genes Dev. 1993;7(11):2063. DOI:10.1101/gad.7.11.2063
23. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986;46(5):705-16. DOI:10.1016/0092-8674(86)90346-6
24. Llona-Minguez S, Baiget J, Mackay SP. Small-molecule inhibitors of IkappaB kinase (IKK) and IKK-related kinases. Pharm Pat Anal. 2013;2(4):481-98. DOI:10.4155/ppa.13.31
25. Carter RS, Pennington KN, Ungurait BJ, Ballard DW. In vivo identification of inducible phosphoacceptors in the IKKgamma/NEMO subunit of human IkappaB kinase. J Biol Chem. 2003;278(22):19642-8. DOI:10.1074/jbc.M301705200
26. Bian Y, Song C, Cheng K, et al. An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014;96:253-62. DOI:10.1016/j.jprot.2013.11.014
27. Fu X, Xu M, Song Y, et al. Enhanced interaction between SEC2 mutant and TCR Vβ induces MHC II-independent activation of T cells via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways. J Biol Chem. 2018;293(51):19771-84. DOI:10.1074/jbc.RA118.003668
28. Yamamoto T, Tsutsumi N, Tochio H, et al. Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Mol Immunol. 2014;58(1):66-76. DOI:10.1016/J.MOLIMM.2013.11.008
29. George J, Motshwene PG, Wang H, et al. Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly.
J Biol Chem. 2011;286(2):1341-53. DOI:10.1074/jbc.M110.159996
30. Balakrishnan A, Vyas A, Deshpande K, Vyas D. Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer. World J Gastroenterol. 2016;22(7):2159-64. DOI:10.3748/wjg.v22.i7.2159
31. Daub H, Olsen JV, Bairlein M, et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008;31(3):438-48. DOI:10.1016/j.molcel.2008.07.007
32. Zhou H, Di Palma S, Preisinger C, et al. Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013;12(1):260-71. DOI:10.1021/pr300630k

Авторы

О.А. Громова*¹, М.В. Филимонова^2,3, И.Ю. Торшин¹, Д.Е. Фролова^1,4

¹ФГУ «Федеральный исследовательский центр "Информатика и управление" Российской академии наук», Москва, Россия;
²ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России, Москва, Россия;
³Медицинский радиологический научный центр им. А.Ф. Цыба – филиал ФГБУ «НМИЦ радиологии» Минздрава России, Обнинск, Россия;
⁴ФГБОУ ВО «Ивановский государственный медицинский университет» Минздрава России, Иваново, Россия
*unesco.gromova@gmail.com

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Olga A. Gromova*¹, Marina V. Filimonova^2,3, Ivan Yu. Torshin¹, Daria Е. Frolova^1,4

¹Federal Research Center "Computer Science and Control" of the Russian Academy of Sciences, Moscow, Russia;
²National Medical Research Radiological Centre, Moscow, Russia;
³Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Centre, Obninsk, Russia;
⁴Ivanovo State Medical University, Ivanovo, Russia
*unesco.gromova@gmail.com

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