酪氨酸激酶抑制剂调控宿主抗结核作用的研究进展

doi:10.19982/j.issn.1000-6621.20240079

摘要/Abstract

摘要：

尽管现有的抗结核治疗方案在药物敏感结核病患者的治疗中取得了显著成效,但是药物毒性及耐药菌株的问题日益突出。因此,研究者们开始寻找新的药物和治疗策略,以期更好地治疗结核病。宿主导向治疗(host-directed therapy,HDT)可利用小分子化合物调节宿主的免疫反应,进而保护组织并清除病原体。HDT的主要目的是增强宿主的抗结核免疫功能,同时缩短传统抗生素治疗的时间,提高治疗效果,被视为治疗结核病的一种有前景的方法。酪氨酸激酶(protein tyrosine kinase,PTK)主要参与激活细胞信号转导,从而调节细胞生长、增殖、死亡等一系列生理生化过程。酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)是一种新型抗癌药物,在多种恶性肿瘤中可靶向过表达细胞通路,也可通过诱导自噬并激活其他信号通路发挥抗肿瘤活性。研究发现,TKI也可以在巨噬细胞中调节信号转导过程,降低胞内结核分枝杆菌的载量,具有巨大的治疗潜力。因此,TKI可作为HDT的潜在候选药物,应用于临床辅助治疗结核病。笔者将从PTK及信号转导入手,针对潜在的HDT治疗结核病的靶向药物研究进行综述,旨在为HDT疗法更好地应用于现有药物及研发新药,从而辅助治疗结核病提供参考。

关键词: 结核, 抗结核药, 宿主与病原体相互作用, 蛋白酪氨酸激酶类

Abstract:

Although existing anti-tuberculosis treatment regimens have achieved remarkable results in the treatment of patients with drug-susceptible tuberculosis, the problems of drug toxicity and resistant strains are increasingly prominent. As a result, new drugs and treatment strategies are developed to better treat tuberculosis. Host-directed therapy (HDT) uses small molecule compounds to modulate the host’s immune response, thereby to protect tissues and eliminate pathogens. The main purpose of HDT is to enhance the host’s anti-tuberculosis immune function while shorten the duration of traditional antibiotic therapy and improve the treatment effect, which is regarded as a promising method for the treatment of tuberculosis. Tyrosine kinase (PTK) is mainly involved in activating cell signal transduction, to regulate a series of physiological and biochemical processes such as cell growth, proliferation, and death. Tyrosine kinase inhibitor (TKI) is a novel anticancer drug that can target overexpressed cellular pathways in a variety of malignant tumors, and can also exert antitumor activity by inducing autophagy and activating other signaling pathways. It has been found that TKI can also regulate the signal transduction process in macrophages and reduce the intracellular Mycobacterium tuberculosis (MTB) load, which has great therapeutic potential. Therefore, TKI can be used as potential candidates for HDT in the clinical adjuvant treatment of tuberculosis. In this paper, the potential targeted drug research for the treatment of tuberculosis by transferring PTK and signaling were reviewed, aiming to provide a reference for better application of existing drugs and the development of new drugs for the treatment of tuberculosis.

Key words: Tuberculosis, Antitubercular agents, Host-pathogen interactions, Protein-tyrosine kinases

中图分类号:

R521
R392

段淑娟, 王伟, 逄宇, 李凌. 酪氨酸激酶抑制剂调控宿主抗结核作用的研究进展[J]. 中国防痨杂志, 2024, 46(5): 584-589. doi: 10.19982/j.issn.1000-6621.20240079

Duan Shujuan, Wang Wei, Pang Yu, Li Ling. Research progress on the regulation of host anti-tuberculosis effect by tyrosine kinase inhibitors[J]. Chinese Journal of Antituberculosis, 2024, 46(5): 584-589. doi: 10.19982/j.issn.1000-6621.20240079

图/表 2

参考文献 44

[1]	舒薇, 刘宇红. 世界卫生组织《2023年全球结核病报告》解读. 结核与肺部疾病杂志, 2024, 5(1): 15-19. doi:10.19983/j.issn.2096-8493.2024006.
[2]	虞翔, 吴叶鉴, 冀磊. 宿主导向的抗菌和抗病毒治疗. 国外医药抗生素分册, 2018, 39(6): 507-521. doi:10.13461/j.cnki.wna.005152.
[3]	Paik S, Kim JK, Chung C, et al. Autophagy: A new strategy for host-directed therapy of tuberculosis. Virulence, 2019, 10(1): 448-459. doi:10.1080/21505594.2018.1536598. pmid: 30322337
[4]	Jeong EK, Lee HJ, Jung YJ. Host-Directed Therapies for Tuberculosis. Pathogens, 2022, 11(11): 1291. doi:10.3390/pathogens11111291.
[5]	Kilinç G, Saris A, Ottenhoff THM, et al. Host-directed therapy to combat mycobacterial infections. Immunol Rev, 2021, 301(1): 62-83. doi:10.1111/imr.12951. pmid: 33565103
[6]	Hu Y, Wen Z, Liu S, et al. Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy. J Infect, 2020, 80(6): e19-e26. doi:10.1016/j.jinf.2020.03.003.
[7]	董雪迎, 梁凯, 叶克应, 等. 受体酪氨酸激酶对自噬的调控及其研究进展. 中国生物工程杂志, 2021, 41(5): 72-78. doi:10.13523/j.cb.2012041.
[8]	Jiao Q, Bi L, Ren Y, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer, 2018, 17(1): 36. doi:10.1186/s12943-018-0801-5. pmid: 29455664
[9]	张迎秋, 刘书言, 刘晗. 受体酪氨酸激酶ErbB2靶向治疗策略和内吞降解调控的研究进展. 中国科学: 生命科学, 2021, 51(12): 1668-1680. doi:10.1360/SSV-2021-0410.
[10]	Cortese M, Kumar A, Matula P, et al. Reciprocal Effects of Fibroblast Growth Factor Receptor Signaling on Dengue Virus Replication and Virion Production. Cell Rep, 2019, 27(9): 2579-2592.e6. doi:10.1016/j.celrep.2019.04.105. pmid: 31141684
[11]	Tavares NC, Gava SG, Torres GP, et al. Schistosoma mansoni FES Tyrosine Kinase Involvement in the Mammalian Schistosomiasis Outcome and Miracidia Infection Capability in Biomphalaria glabrata. Front Microbiol, 2020, 11: 963. doi:10.3389/fmicb.2020.00963. pmid: 32595609
[12]	Rodríguez-Mora S, Spivak AM, Szaniawski MA, et al. Tyrosine Kinase Inhibition: a New Perspective in the Fight against HIV. Curr HIV/AIDS Rep, 2019, 16(5): 414-422. doi:10.1007/s11904-019-00462-5.
[13]	Volinsky N, Kholodenko BN. Complexity of receptor tyrosine kinase signal processing. Cold Spring Harb Perspect Biol, 2013, 5(8): a009043. doi:10.1101/cshperspect.a009043.
[14]	Neben CL, Lo M, Jura N, et al. Feedback regulation of RTK signaling in development. Dev Biol, 2019, 447(1): 71-89. doi:10.1016/j.ydbio.2017.10.017. pmid: 29079424
[15]	Rodríguez-Hernández MA, de la Cruz-Ojeda P, López-Grueso MJ, et al. Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer. Redox Biol, 2020, 36: 101510. doi:10.1016/j.redox.2020.101510.
[16]	Critchley WR, Pellet-Many C, Ringham-Terry B, et al. Receptor Tyrosine Kinase Ubiquitination and De-Ubiquitination in Signal Transduction and Receptor Trafficking. Cells, 2018, 7(3): 22. doi:10.3390/cells7030022.
[17]	Carter JL, Hege K, Yang J, et al. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther, 2020, 5(1): 288. doi:10.1038/s41392-020-00361-x.
[18]	Chabot T, Cheraud Y, Fleury F. Relationships between DNA repair and RTK-mediated signaling pathways. Biochim Biophys Acta Rev Cancer, 2021, 1875(1): 188495. doi:10.1016/j.bbcan.2020.188495.
[19]	Margiotta A. All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal. Int J Mol Sci, 2021, 22(12): 6342. doi:10.3390/ijms22126342.
[20]	Saraon P, Pathmanathan S, Snider J, et al. Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches. Oncogene, 2021, 40(24): 4079-4093. doi:10.1038/s41388-021-01841-2. pmid: 34079087
[21]	Sudhesh Dev S, Zainal Abidin SA, Farghadani R, et al. Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer. Front Pharmacol, 2021, 12: 772510. doi:10.3389/fphar.2021.772510.
[22]	Azad T, Rezaei R, Surendran A, et al. Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis. Cancers (Basel), 2020, 12(8): 2042. doi:10.3390/cancers12082042.
[23]	Wang X, Li W, Zhang N, et al. Opportunities and challenges of co-targeting epidermal growth factor receptor and autophagy signaling in non-small cell lung cancer. Oncol Lett, 2019, 18(1): 499-506. doi:10.3892/ol.2019.10372. pmid: 31289521
[24]	Liu S, Liao Y, Chen B, et al. Critical role of Syk-dependent STAT1 activation in innate antiviral immunity. Cell Rep, 2021, 34(3): 108627. doi:10.1016/j.celrep.2020.108627.
[25]	Bermejo M, López-Huertas MR, García-Pérez J, et al. Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4⁺ T cells. Biochem Pharmacol, 2016, 106: 30-45. doi:10.1016/j.bcp.2016.02.002.
[26]	张其程, 徐克. 自噬在EGFR-TKI类肿瘤靶向药物对肺癌的治疗和耐药中作用的研究进展. 中国肺癌杂志, 2016, 19(9): 607-614. doi:10.3779/j.issn.1009-3419.2016.09.09.
[27]	Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell, 2010, 141(7): 1117-1134. doi:10.1016/j.cell.2010.06.011. pmid: 20602996
[28]	Botti J, Djavaheri-Mergny M, Pilatte Y, et al. Autophagy signaling and the cogwheels of cancer. Autophagy, 2006, 2(2): 67-73. doi:10.4161/auto.2.2.2458. pmid: 16874041
[29]	Wei Y, Zou Z, Becker N, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell, 2013, 154(6): 1269-1284. doi:10.1016/j.cell.2013.08.015. pmid: 24034250
[30]	Mukherjee T, Bhatt B, Prakhar P, et al. Epigenetic reader BRD 4 supports mycobacterial pathogenesis by co-modulating host lipophagy and angiogenesis. Autophagy, 2022, 18(2): 391-408. doi:10.1080/15548627.2021.1936355.
[31]	Sogi KM, Lien KA, Johnson JR, et al. The Tyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth through Increased Lysosomal Biogenesis and Modulation of Cytokine Signaling. ACS Infect Dis, 2017, 3(8): 564-574. doi:10.1021/acsinfecdis.7b00046.
[32]	Salisbury TB, Tomblin JK. Insulin/Insulin-like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms, and new blocking strategies. Front Endocrinol (Lausanne), 2015, 6: 12. doi:10.3389/fendo.2015.00012.
[33]	De Martino MC, van Koetsveld PM, Feelders RA, et al. IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer. Endocrine, 2019, 64(3): 673-684. doi:10.1007/s12020-019-01869-1.
[34]	Rodrigues Alves APN, Fernandes JC, Fenerich BA, et al. IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells. Cancer Lett, 2019, 456: 59-68. doi:10.1016/j.canlet.2019.04.030. pmid: 31042587
[35]	Wang H, Bi J, Zhang Y, et al. Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis. ACS Infect Dis, 2022, 8(10): 2019-2027. doi:10.1021/acsinfecdis.2c00278.
[36]	Woodring PJ, Litwack ED, O’Leary DD, et al. Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension. J Cell Biol, 2002, 156(5): 879-892. doi:10.1083/jcb.200110014. pmid: 11864995
[37]	Appel S, Rupf A, Weck MM, et al. Effects of imatinib on monocyte-derived dendritic cells are mediated by inhibition of nuclear factor-kappaB and Akt signaling pathways. Clin Cancer Res, 2005, 11(5): 1928-1940. doi:10.1158/1078-0432.CCR-04-1713. pmid: 15756019
[38]	Bruns H, Stegelmann F, Fabri M, et al. Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages. J Immunol, 2012, 189(8): 4069-4078. doi:10.4049/jimmunol.1201538.
[39]	Kuijl C, Savage ND, Marsman M, et al. Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature, 2007, 450(7170): 725-730. doi:10.1038/nature06345.
[40]	Hussain T, Zhao D, Shah SZA, et al. Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy. Cells, 2019, 8(5): 506. doi:10.3390/cells8050506.
[41]	Purcaru OS, Artene SA, Barcan E, et al. The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer. Int J Mol Sci, 2021, 22(9): 4830. doi:10.3390/ijms22094830.
[42]	Colado A, Genoula M, Cougoule C, et al. Effect of the BTK inhibitor ibrutinib on macrophage- and γδ T cell-mediated response against Mycobacterium tuberculosis. Blood Cancer J, 2018, 8(11): 100. doi:10.1038/s41408-018-0136-x. pmid: 30397191
[43]	Sun FD, Wang PC, Shang J, et al. Ibrutinib presents antitumor activity in skin cancer and induces autophagy. Eur Rev Med Pharmacol Sci, 2018, 22(2): 561-566. doi:10.26355/eurrev_201801_14210.
[44]	Wang J, Liu X, Hong Y, et al. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma. J Exp Clin Cancer Res, 2017, 36(1): 96. doi:10.1186/s13046-017-0549-6. pmid: 28716053