Acta NaturaeActa NaturaeActa Naturae2075-8251Acta Naturae Ltd2764910.32607/actanaturae.27649Research ArticlesЭкспериментальные статьиResearch ArticleQuantification of the synergism between HER-targeted drugs with human blood serum and EGFКоличественная оценка синергического взаимодействия противоопухолевых препаратов с сывороткой крови и с эпидермальным фактором роста человекаKamashevD. E.КамашевД. Э.
Russian Federation

World-Class Research Center “Digital Biodesign and Personalized Healthcare”

Научно-исследовательский центр мирового класса «Цифровой биодизайн и персонализированное здравоохранение»

dkamashev@gmail.comLeboshchinaE. M.ЛебощинаЕ. М.
Russian Federation
dkamashev@gmail.comKoleboshinaA. V.КолебошинаА. В.
Russian Federation
dkamashev@gmail.comLavrinenkoI. A.ЛавриненкоИ. А.
Russian Federation
dkamashev@gmail.comVashanovG. A.ВашановГ. А.
Russian Federation
dkamashev@gmail.comNechipurenkoYu. D.НечипуренкоЮ. Д.
Russian Federation
dkamashev@gmail.comShemyakin–Ovchinnikov Institute of Bioorganic ChemistryГосударственный научный центр Институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАНSechenov First Moscow State Medical UniversityПервый Московский государственный медицинский университет им. И.М. Сеченова МЗ РФ (Сеченовский университет)Moscow Institute of Physics and TechnologyМосковский физико-технический институтVoronezh State UniversityВоронежский государственный университетEngelhardt Institute of Molecular BiologyИнститут молекулярной биологии им. В.А. Энгельгардта РАН2204202618146540403202520082025Copyright ©; 2026, Kamashev D.E., Leboshchina E.M., Koleboshina A.V., Lavrinenko I.A., Vashanov G.A., Nechipurenko Y.D.Copyright ©; 2026, Камашев Д.Э., Лебощина Е.М., Колебошина А.В., Лавриненко И.А., Вашанов Г.А., Нечипуренко Ю.Д.2026Kamashev D.E., Leboshchina E.M., Koleboshina A.V., Lavrinenko I.A., Vashanov G.A., Nechipurenko Y.D.Камашев Д.Э., Лебощина Е.М., Колебошина А.В., Лавриненко И.А., Вашанов Г.А., Нечипуренко Ю.Д.https://creativecommons.org/licenses/by/4.0https://actanaturae.ru/2075-8251/article/view/27649

Finding the optimal combination of drugs for the effective inhibition of cancer cell growth is an extremely important task today, as the number of such drugs continues to grow. There are several approaches to determining the nature of drug interactions, allowing one to establish whether they are additive, synergistic, or antagonistic. One such approach is described here, and it is demonstrated how to quantitatively measure the degree of interaction between two drugs. It is shown that human peripheral blood serum and EGF modulate the activity of HER2-targeted drugs in inhibiting the proliferation of HER2-positive BT474 and SK-BR-3 cells. We compared the effect of blood serum samples from breast cancer (BC) patients and healthy donors on the action of trastuzumab. Using the proposed method, it is possible to calculate the Combination Index (CI). For 17 serum samples from healthy donors, the mean CI was 0.396, while for 19 serum samples from patients with BC, the mean CI was 0.214. These results indicate a synergistic interaction between trastuzumab and blood serum in both groups. We also found significant differences in CI values between healthy donors and breast cancer patients: blood serum samples from patients enhance the effect of trastuzumab to a greater extent.

Поиск оптимальной комбинации лекарственных препаратов для эффективного ингибирования роста опухолевых клеток – крайне актуальная задача сейчас, когда таких препаратов становится все больше. Существует несколько подходов к определению характера взаимодействия препаратов, позволяющих установить, является ли оно аддитивным, синергическим или антагонистическим. Здесь описан один из таких подходов и показано, как количественно измерить степень взаимодействия двух препаратов. Показано, что сыворотка периферической крови человека и EGF модулируют активность HER2-таргетных препаратов в ингибировании пролиферации HER2-положительных линий клеток BT474 и SK-BR-3. Проведено сравнение влияния образцов сыворотки крови пациентов с раком молочной железы (РМЖ) и здоровых доноров на действие трастузумаба. Предложенный метод позволяет рассчитать индекс взаимодействия препаратов (CI, Combination Index). Среднее значение CI, рассчитанное для 17 образцов сыворотки здоровых доноров, составило 0.396, тогда как у 19 образцов сыворотки пациентов с РМЖ среднее значение CI оказалось равным 0.214. Эти результаты свидетельствуют о синергическом взаимодействии трастузумаба с сывороткой крови в обеих группах. Обнаружены значимые различия в величинах CI между группами здоровых доноров и пациентов с РМЖ: образцы сыворотки крови пациентов усиливали действие трастузумаба в большей степени.

targeted therapyHER2breast cancerhuman blood serumtrastuzumablapatinibтаргетная терапияHER2рак молочной железысыворотка крови человекатрастузумаблапатинибМинистерство науки и высшего образования Российской ФедерацииMinistry of Science and Higher Education of the Russian Federation075-00251-24-00This work was supported in part by the Ministry of Science and Higher Education of the Russian Federation, project No. 124031500019-8.Работа частично выполнена при финансовой поддержке Министерства науки и высшего образования РФ в рамках НИОКТР (Госзадания) 124031500019-8.Voit EO, Martens HA, Omholt SW. 150 years of the mass action law. PLoS Comput Biol. 2015;11(1):e1004012. doi: 10.1371/journal.pcbi.1004012Ferner RE, Aronson JK. Cato Guldberg and Peter Waage, the history of the Law of Mass Action, and its relevance to clinical pharmacology. Br J Clin Pharmacol. 2016;81(1):52-55. doi: 10.1111/bcp.12721Hüfner G. Ueber das Gesetz der Dissociation des Oxyhaemoglobins und über einige daran sich knüpfende wichtige Fragen aus der Biologie. Arch Physiol. 1890;31:1-27.Michaelis L, Menten ML. Die kinetik der invertinwirkung. Biochem Z. 1913;49:333-369.Michaelis L, Menten ML. Die kinetik der invertinwirkung. Biochem z. 1913;49(333-369):352.Langmuir I. The constitution and fundamental properties of solids and liquids. Part I. Solids. J Amer Chem Soc. 1916;38(11):2221-2295. doi: 10.1021/ja02268a002Langmuir I. The constitution and fundamental properties of solids and liquids. Part I. Solids. J Amer Chem Soc. 1916;38(11):2221-2295.Hill AV. The possible effects of the aggregation of the molecules of hæmoglobin on its dissociation curves. J Physiol. 1910;40:iv-vii.Hill AV. The possible effects of the aggregation of the molecules of hæmoglobin on its dissociation curves. J of Phys. 1910;40:i--vii.Endrenyi L, Fajszi C, Kwong FH. Evaluation of Hill slopes and Hill coefficients when the saturation binding or velocity is not known. Eur J Biochem. 1975;51(2):317-328. doi: 10.1111/j.1432-1033.1975.tb03931.xEndrenyi L, Fajszi C, Kwong FH. Evaluation of Hill slopes and Hill coefficients when the saturation binding or velocity is not known. Eur J Biochem. 1975;51(2):317-28. doi: 10.1111/j.1432-1033.1975.tb03931.xWeiss JN. The Hill equation revisited: uses and misuses. FASEB J. 1997;11(11):835-841. doi: 10.1096/fasebj.11.11.9285481Lavrinenko IA, Vashanov GA, Nechipurenko YD. New Interpretation of the Hill Coefficient. Biophysics. 2022;67:171-174. doi: 10.1134/S0006350922020142Lavrinenko IA, Vashanov GA, Nechipurenko YD. New Interpretation of the Hill Coefficient. Biophysics. 2022;67(2):171-174. doi: 10.1134/S0006350922020142Bordbar AK, Saadati Z, Sohrabi N. Analysis of ligand binding process using binding capacity concept. Acta Biochim Pol. 2004;51(4):963-970. doi: 10.18388/abp.2004_3529Srinivasan S, Waghu FH, Idicula-Thomas S, Venkatesh KV. A steady-state modeling approach for simulation of antimicrobial peptide-cell membrane interaction. Biochim Biophys Acta Biomembr. 2020;1862(4):183242. doi: 10.1016/j.bbamem.2020.183242Srinivasan S, Waghu FH, Idicula-Thomas S, Venkatesh KV. A steady-state modeling approach for simulation of antimicrobial peptide-cell membrane interaction. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2020;1862(4):183242. doi: 10.1016/j.bbamem.2020.183242Lavrinenko IA, Vashanov GA, Buchelnikov AS, Nechipurenko YD. Cooperative Oxygen Binding with Hemoglobin as a General Model in Molecular Biophysics. Biophysics. 2022;67:327-337. doi: 10.1134/S0006350922030113Lavrinenko IA, Vashanov GA, Buchelnikov AS, Nechipurenko YD. Cooperative Oxygen Binding with Hemoglobin as a General Model in Molecular Biophysics. Biophysics. 2022;67(3):327-337. doi: 10.1134/S0006350922030113Lavrinenko IA, Vashanov GA, Hernandez Caceres JL, Nechipurenko YD. Mathematical models describing oxygen binding by hemoglobin. Biophys Rev. 2023;15(5):1269-1278. doi: 10.1007/s12551-023-01110-4Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27-55. doi: 10.1016/0065-2571(84)90007-4Goutelle S, Maurin M, Rougier F, et al. The Hill equation: a review of its capabilities in pharmacological modelling. Fundam Clin Pharmacol. 2008;22(6):633-648. doi: 10.1111/j.1472-8206.2008.00633.xGoutelle S, Maurin M, Rougier F, et al. The Hill equation: a review of its capabilities in pharmacological modelling. Fundamental & Clinical Pharmacology. 2008;22(6):633-648. doi: 10.1111/j.1472-8206.2008.00633.xChang JB, Quinnies KM, Realubit R, et al. A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient. Sci Rep. 2016;6:29387. doi: 10.1038/srep29387Chang JB, Quinnies KM, Realubit R, et al. A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient. Scientific Reports. 2016;6(1):29387. doi: 10.1038/srep29387Lavrinenko IA, Vashanov GA, Nechipurenko YD. New Mathematical Model to Describe Hemoglobin Oxygenation. Biophysics. 2022;67:347-352. doi: 10.1134/S0006350922030125Lavrinenko IA, Vashanov GA, Nechipurenko YD. New Mathematical Model to Describe Hemoglobin Oxygenation. Biophysics. 2022;67(3):347-352. doi: 10.1134/S0006350922030125Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621-681. doi: 10.1124/pr.58.3.10Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. Sep 2006;58(3):621-681. doi: 10.1124/pr.58.3.10Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440-446. doi: 10.1158/0008-5472.CAN-09-1947Chou TC. Multidisciplinary examples of applications: Papers using the MAL-PD/BD/CI/BI theory/method. In: Chou TC, ed. Mass-Action Law Dynamics Theory and Algorithm for Translational and Precision Medicine Informatics. Academic Press; 2024:181-218.Chou T-C. Chapter X - Multidisciplinary examples of applications: Papers using the MAL-PD/BD/CI/BI theory/method. In: Chou T-C, ed. Mass-Action Law Dynamics Theory and Algorithm for Translational and Precision Medicine Informatics. Academic Press; 2024:181-218.Greco W, Unkelbach HD, Pöch G, Sühnel J, Kundi M, Bödeker W. Consensus on concepts and terminology for combined-action assessment: The Saariselkä agreement. Arch Complex Environ Stud. 1992;4:65-69.Greco W, Unkelbach HD, Pöch G, et al. Consensus on concepts and terminology for combined-action assessment: The Saariselkä agreement. Arch Complex Environ Stud. 1992;4:65-69.Bliss CI. The toxicity of poisons applied jointly. Ann Appl Biol. 1939;26(3):585-615. doi: 10.1111/j.1744-7348.1939.tb06990.xBliss CI. The toxicity of poisons applied jointly. Annals of Applied Biology. 1939;26(3):585-615. doi: 10.1111/j.1744-7348.1939.tb06990.xLoewe S, Muischnek H. Über Kombinationswirkungen. Naunyn Schmiedebergs Arch Pharmacol. 1926;114:313-326. doi: 10.1007/BF01952257Loewe S, Muischnek H. Über Kombinationswirkungen. Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie. 1926;114(5):313-326. doi: 10.1007/BF01952257Kamashev D, Shaban N, Zakharova G, et al. Lapatinib-induced enhancement of mitochondrial respiration in HER2-positive SK-BR-3 cells: mechanism revealed by analysis of proteomic but not transcriptomic data. Front Mol Biosci. 2024;11:1470496. doi: 10.3389/fmolb.2024.1470496Kamashev D, Sorokin M, Kochergina I, et al. Human blood serum can donor-specifically antagonize effects of EGFR-targeted drugs on squamous carcinoma cell growth. Heliyon. 2021;7(3):e06394. doi: 10.1016/j.heliyon.2021.e06394Kamashev D, Sorokin M, Kochergina I, et al. Human blood serum can donor-specifically antagonize effects of EGFR-targeted drugs on squamous carcinoma cell growth. Heliyon. Mar 2021;7(3):e06394. doi: 10.1016/j.heliyon.2021.e06394Geissmann Q. OpenCFU, a new free and open-source software to count cell colonies and other circular objects. PLoS One. 2013;8(2):e54072. doi: 10.1371/journal.pone.0054072Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 2004;44:195-217. doi: 10.1146/annurev.pharmtox.44.101802.121440Yamaoka T, Kusumoto S, Ando K, Ohba M, Ohmori T. Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int J Mol Sci. 2018;19(11). doi: 10.3390/ijms19113491Yamaoka T, Kusumoto S, Ando K, et al. Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int J Mol Sci. 2018;19(11). doi: 10.3390/ijms19113491Asif HM, Sultana S, Ahmed S, Akhtar N, Tariq M. HER-2 Positive Breast Cancer - a Mini-Review. Asian Pac J Cancer Prev. 2016;17(4):1609-1615. doi: 10.7314/apjcp.2016.17.4.1609Asif HM, Sultana S, Ahmed S, et al. HER-2 Positive Breast Cancer - a Mini-Review. Asian Pac J Cancer Prev. 2016;17(4):1609-1615. doi: 10.7314/apjcp.2016.17.4.1609Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754. doi: 10.1016/S1470-2045(17)30313-3Shaban N, Kamashev D, Emelianova A, Buzdin A. Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications. Cells. 2023;13(1):47. doi: 10.3390/cells13010047Shaban N, Kamashev D, Emelianova A, Buzdin A. Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications. Cells. 2023;13(1). doi: 10.3390/cells13010047Kamashev D, Shaban N, Lebedev T, et al. Human Blood Serum Can Diminish EGFR-Targeted Inhibition of Squamous Carcinoma Cell Growth through Reactivation of MAPK and EGFR Pathways. Cells. 2023;12(16):2022. doi: 10.3390/cells12162022Kamashev D, Shaban N, Lebedev T, et al. Human Blood Serum Can Diminish EGFR-Targeted Inhibition of Squamous Carcinoma Cell Growth through Reactivation of MAPK and EGFR Pathways. Cells. 2023;12(16). doi: 10.3390/cells12162022Diermeier S, Horváth G, Knuechel-Clarke R, Hofstaedter F, Szöllosi J, Brockhoff G. Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation. Exp Cell Res. 2005;304(2):604-619. doi: 10.1016/j.yexcr.2004.12.008Diermeier S, Horvath G, Knuechel-Clarke R, et al. Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation. Exp Cell Res. 2005;304(2):604-619. doi: 10.1016/j.yexcr.2004.12.008Kamashev D, Shaban N, Suntsova M, et al. Human Blood Serum Inhibits Ductal Carcinoma Cells BT474 Growth and Modulates Effect of HER2 Inhibition. Biomedicines. 2022;10(8):1914. doi: 10.3390/biomedicines10081914Kamashev D, Shaban N, Suntsova M, et al. Human Blood Serum Inhibits Ductal Carcinoma Cells BT474 Growth and Modulates Effect of HER2 Inhibition. Biomedicines. 2022;10(8). doi: 10.3390/biomedicines10081914