mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-POT-2303mimmun-2459Research ArticleОБЗОРЫREVIEWSПептиды врожденного иммунитета как потенциальные противоопухолевые агенты: плюсы и минусыPeptides of the innate immunity as potential anticancer agents: pros and consЧерновА. Н.ChernovA. N.

Чернов Александр Николаевич – научный сотрудник отдела общей патологии и патологической физиологии.

197376, Санкт-Петербург, ул. Акад. Павлова, 12. Тел.: 8 (960) 270-43-97

Chernov Alexander N. - Research Associate, Department of General Pathology and Pathological Physiology.

197376, St. Petersburg, Acad. Pavlov str., 12. Phone: 7 (960) 270-43-97

al.chernov@mail.ruОрловД. С.OrlovD. S.

Кандидат медицинских наук, доцент, заведующий лабораторией иммунопатофизиологии отдела общей патологии и патологической физиологии.

Санкт-Петербург

PhD (Medicine), Associate Professor, Head, Laboratory of Immunopathophysiology, Department of General Pathology and Pathological Physiology.

St. Petersburg

ШамоваО. В.ShamovaO. V.

Доктор биологических наук, доцент, член-корр. РАН, заведующая отделом общей патологии и патологической физиологии, заместитель директора по научной работе

Санкт-Петербург

PhD, MD (Biology), Associate Professor, Corresponding Member, Russian Academy of Sciences, Head, Department of General Pathology and Pathological Physiology, Deputy Director for Research IEM; Professor, Department of Biochemistry, Faculty of Biology, St. Petersburg SU.

St. Petersburg

ФГБНУ Институт экспериментальной медициныРоссияInstitute of Experimental MedicineRussian FederationФГБНУ Институт экспериментальной медицины; ФГБОУ ВО Санкт-Петербургский государственный университетРоссияInstitute of Experimental Medicine; St. Petersburg State UniversityRussian Federation20212112202123612851306Copyright © Чернов А.Н., Орлов Д.С., Шамова О.В., 20212021Чернов А.Н., Орлов Д.С., Шамова О.В.Chernov A.N., Orlov D.S., Shamova O.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2459

Онкологические заболевания представляют серьезную социально-экономическую проблему. Основным подходом к терапии опухолей является их хирургическая резекция, часто дополняемая лучевой и химиотерапией. Эффективность такого комплексного лечения во многих случаях остается невысокой. В связи с этим возникает острая необходимость поиска новых соединений, обладающих селективной цитотоксической активностью в отношении опухолевых клеток и не повреждающих нормальные ткани организма. В обзоре рассматриваются механизмы противоопухолевого действия катионных антимикробных пептидов (АМП) семейства кателицидинов – α-спирального кателицидина человека (LL-37) и пептида с конформацией β-шпильки – протегрина-1 (PG-1) на клетки рака легкого, молочной, поджелудочной, предстательной желез, меланомы, плоскоклеточного рака кожи, полости рта, желудка, яичников, колоректального рака, лейкозов, лимфом, глиом и нейробластом. Обсуждается возможность противоопухолевого и противоположного – проонкогенного действия пептидов и взаимосвязь этих эффектов c иммуномодулирующей активностью АМП на опухоль-ассоциированные макрофаги, естественные киллерные клетки и T-лимфоциты. Приводятся возможные механизмы селективного действия LL-37 и PG-1 на опухолевые клетки, включающее взаимодействие LL-37 с G-белок-связанными рецепторами: N-формилпептида-2 (FPR2), CXC хемокина-2 (CXCR2), Mas-ассоциированным с геном X (MrgX2), пуринергическим (P2Y11), эпидермального (EGFR/ErbB1, ERBb2), инсулино-подобного (IGF1R) факторов роста, лиганд-управляемых ионных каналов (LGIC) и Toll-подобными (TLR) рецепторами, экспрессия которых значительно изменяется в разных типах опухолей по сравнению с нормой. Однако при этом особенно важно учитывать, что терапевтические эффекты LL-37 и его производных могут использоваться только для конкретных типов опухолей. Механизмы действия PG-1 на опухолевые клетки остаются еще плохо изученными, хотя имеющиеся данные свидетельствуют, что протегрин проявляет более однонаправленное действие – повреждает мембраны. Протегрин-1 и LL-37 могут синергически усиливать противоопухолевые эффекты химиопрепаратов и оказывают более выраженное действие на опухолевые, чем на нормальные клетки. Природные АМП представляются перспективными кандидатами на роль новых противоопухолевых средств, которые проявляют активность и в отношении злокачественных метастазирующих, рецидивирующих опухолей с множественной лекарственной устойчивостью. С другой стороны, такие пептиды, как LL-37, проявляют в некоторых случаях свойства, которые могут рас- сматриваться как проонкогенные, что указывает на необходимость дальнейшего детального изучения молекулярных механизмов их действия на опухолевые клетки.

Surgical resection was the main approach to cancer therapy, often supplemented by radiation and chemotherapy. The effectiveness of such complex treatment in many cases remains low. In this regard, there is an urgent need to search for new compounds that have selective cytotoxic activity against tumor cells and do not damage normal tissues of the organism. The review discusses mechanisms of antitumor action of cationic antimicrobial peptides (AMPs) of the cathelicidin family - human α-helical cathelicidin (LL-37), and a peptide with β-hairpin conformation – protegrin-1 (PG-1) on lung, breast, pancreas, prostate, squamous skin cancer cells, oral cancer, stomach, ovarian, colorectal cancer, melanoma, leukemia, lymphoma, glioma and neuroblastoma cells. An opportunity of antitumor and pro-oncogenic actions of the peptides and an interplay of these effects with mmunomodulatory action of AMPs on tumor-associated macrophages, natural killer cells and T-lymphocytes is discussed. Possible mechanisms of LL-37 and PG-1 selective action upon tumor cells are presented, including the interaction of LL-37 with G-protein-coupled receptors: the N formylpeptide-2 receptor (FPR2), CXC chemokine-2 (CXCR2), Mas-related gene X2 (MrgX2), purinergic (P2Y11), epidermal (EGFR/ErbB1, ERBb2), insulin-like (IGF1R) growth factors, ligand-gated ion channels (LGIC) and Tolllike (TLR) receptors, with expression varying significantly in different types of tumors, as compared to normal tissues. An increase in the level of LL-37 secretion and expression of its CAMP gene are associated with progression of lung adenocarcinoma, breast, pancreas, and prostate cancer, ovarian cancer, melanoma, and squamous cell carcinoma of the skin. In contrast, CAMP expression and LL-37 secretion are significantly reduced in gastric cancer cells, oral squamous cell cancer, colorectal cancer, leukemia, lymphomas, gliomas, and SH-SY5Y neuroblastoma. Therefore, therapeutic effects of LL-37 can only be used for specific types of tumors. The mechanisms of action of PG-1 on tumor cells are still poorly understood, although the available data indicate that protegrin exhibits a more unidirectional effect, i.e., it damages cell membranes. Protegrin-1 and LL-37 can synergistically enhance the antitumor effects of chemotherapy drugs and have a more pronounced effect on tumor cells, than upon normal cells. Natural AMPs appear to be promising candidates for the role of new antitumor agents, which are also active against malignant metastatic, recurrent multidrug-resistant tumors. On the other hand, peptides such as LL-37, in some cases, exhibit properties that can be considered pro-oncogenic, which indicates a need for further detailed studies on the molecular mechanisms of their action on tumor cells.

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The authors declare that there are no conflicts of interest present.