山东大学耳鼻喉眼学报 ›› 2023, Vol. 37 ›› Issue (5): 198-205.doi: 10.6040/j.issn.1673-3770.0.2022.279

• 综述 • 上一篇    

铜诱导肿瘤细胞死亡机制及其在肿瘤治疗中的研究进展

黄艳利1,2,李军政1,3   

  1. 1.贵州医科大学 临床医学院, 贵州 贵阳 550004;
    2.暨南大学附属广州红十字会医院 耳鼻咽喉头颈外科, 广东 广州 510220;
    3.南方医科大学珠江医院 耳鼻咽喉头颈外科中心, 广东 广州 510285
  • 发布日期:2023-10-13
  • 通讯作者: 李军政. E-mail:jzli2002@163.com
  • 基金资助:
    广州市科技计划项目-市校(院)联合资助项目(202102010041,202201020067)

The mechanism of copper-induced tumor cell death and its research progress in cancer therapy

HUANG Yanli1,2, LI Junzheng1,3   

  1. 1. Clinical Medical College of Guizhou Medical University, Guiyang 550004, Guizhou, China2. Department of Otorhinolaryngology & Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, Guangdong, China3. Department of Otorhinolaryngology & Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510285, Guangdong, China
  • Published:2023-10-13

摘要: 铜是人体必不可少的微量元素之一,在多种基本生物学功能中起着关键作用,并且受到铜伴侣蛋白及铜转运蛋白的严格调控。铜在肿瘤生长、上皮-间充质转化、肿瘤微环境和转移前生态位的形成中发挥重要作用,因此铜稳态的失衡可影响肿瘤细胞的生长,导致细胞死亡。铜可通过多种方式诱导肿瘤细胞死亡,如诱导活性氧催化氧化应激、抑制泛素-蛋白酶体系统、肿瘤血管的生成受到抑制等,而新近发现的一种新的调节性细胞死亡方式即“铜死亡”与以往已知的细胞死亡机制都有所不同。因此,铜诱导的调节性细胞死亡机制引起了人们的极大关注,并成为肿瘤治疗领域的研究热点。论文综述铜诱导肿瘤细胞死亡机制的研究进展,并回顾铜诱导肿瘤细胞死亡在乳腺癌、结直肠癌、肺癌、前列腺癌等各种肿瘤治疗中的研究进展。

关键词: 铜, 铜死亡, 肿瘤细胞死亡, 铜配合物, 抗肿瘤治疗

Abstract: Copper is an essential trace element in the human body that plays a key role in several basic biological functions. The safe and specific transport of copper is regulated by copper chaperones and copper transporters. Copper plays an important role in tumor growth, epithelial-mesenchymal transition, tumor microenvironment and pre-metastatic niche formation. Disruption of copper homeostasis alters tumor cell growth and leads to cell death. Copper can induce tumor cell death in several ways, such as reactive oxygen species accumulation, proteasome inhibition, and antiangiogenesis. A new form of copper-induced regulated cell death, called “cuprotosis,” differs from previously known cell death mechanisms and has become a research hotspot in the field of tumor therapy. In this paper, recent research on the mechanism of copper-induced tumor cell death is introduced, and recent research of copper-induced tumor cell death in the treatment of breast, colorectal, lung, and prostate cancers is reviewed.

Key words: Copper, Cuprotosis, Tumor Cell Death, Copper Complexes, Anti-tumor Therapy

中图分类号: 

  • R73
[1] Denoyer D, Clatworthy SAS, Cater MA. Copper complexes in cancer therapy[J]. Met Ions Life Sci, 2018,5:18:/books/9783110470734/9783110470734-022/9783110470734-022.xml. doi: 10.1515/9783110470734-022
[2] Jiang Y, Huo Z, Qi X, et al. Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes[J]. Nanomedicine(Lond), 2022, 17(5): 303-324. doi:10.2217/nnm-2021-0374
[3] Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins[J]. Science, 2022, 375(6586): 1254-1261. doi:10.1126/science.abf0529
[4] 朱洁洁, 王华. 铜诱导调节性细胞死亡的作用机制与抗肿瘤治疗的研究进展[J]. 江苏大学学报(医学版), 2022, 32(4): 326-331, 349. doi:10.13312/j.issn.1671-7783.y220122 ZHU Jiejie, WANG Hua. Mechanism of copper-induced regulatory cell death and research progress of anti-tumor therapy[J] Journal of Jiangsu University(Medicine Edition), 2022, 32(4): 326-331, 349. doi:10.13312/j.issn.1671-7783.y220122
[5] Lossow K, Schwarz M, Kipp AP. Are trace element concentrations suitable biomarkers for the diagnosis of cancer? [J]. Redox Biol, 2021, 42: 101900. doi:10.1016/j.redox.2021.101900
[6] Wang WJ, Wang X, Luo JJ, et al. Serum copper level and the copper-to-zinc ratio could be useful in the prediction of lung cancer and its prognosis: a case-control study in northeast China[J]. Nutr Cancer, 2021, 73(10): 1908-1915. doi:10.1080/01635581.2020.1817957
[7] Denoyer D, Masaldan S, la Fontaine S, et al. Targeting copper in cancer therapy: ‘Copper That Cancer’[J]. Metallomics, 2015, 7(11): 1459-1476. doi:10.1039/c5mt00149h
[8] Nagai M, Vo NH, Shin Ogawa L, et al. The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells[J]. Free Radic Biol Med, 2012, 52(10): 2142-2150. doi:10.1016/j.freeradbiomed.2012.03.017
[9] da Silva DA, De Luca A, Squitti R, et al. Copper in tumors and the use of copper-based compounds in cancer treatment[J]. J Inorg Biochem, 2022, 226: 111634. doi:10.1016/j.jinorgbio.2021.111634
[10] 张转, 刘涛, 白治丽, 等. 氧化应激与噪音性聋发病机制及治疗进展[J]. 山东大学耳鼻喉眼学报, 2017, 31(5): 101-103, 106. doi: 10.6040/j.issn.1673-3770.0.2017.185 ZHANG Zhuan, LIU Tao, BAI Zhili, et al. Evolution of oxidative stress in the pathogenesis and treatment of noise-induced hearing loss[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2017, 31(5): 101-103, 106. doi: 10.6040/j.issn.1673-3770.0.2017.185
[11] Jomova K, Hudecova L, Lauro P, et al. The effect of Luteolin on DNA damage mediated by a copper catalyzed Fenton reaction[J]. J Inorg Biochem, 2022, 226: 111635. doi:10.1016/j.jinorgbio.2021.111635
[12] Ngamchuea K, Batchelor-McAuley C, Compton RG. The copper(II)-catalyzed oxidation of glutathione[J]. Chemistry, 2016, 22(44): 15937-15944. doi:10.1002/chem.201603366
[13] Kang Z, Qiao N, Liu G, et al. Copper-induced apoptosis and autophagy through oxidative stress-mediated mitochondrial dysfunction in male germ cells[J]. Toxicol In Vitro, 2019, 61: 104639. doi:10.1016/j.tiv.2019.104639
[14] Zhang Z, Wang H, Yan M, et al. Novel copper complexes as potential proteasome inhibitors for cancer treatment?(Review)[J]. Mol Med Rep, 2017, 15(1): 3-11. doi:10.3892/mmr.2016.6022
[15] Zhou T, Cai Y, Liang L, et al. Discovery of a potent and highly specific β2 proteasome inhibitor from a library of copper complexes[J]. Bioorg Med Chem Lett, 2016, 26(23): 5780-5784. doi:10.1016/j.bmcl.2016.10.043
[16] Han J, Liu L, Yue X, et al. A binuclear complex constituted by diethyldithiocarbamate and copper(I)functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts[J]. Toxicol Appl Pharmacol, 2013, 273(3): 477-483. doi:10.1016/j.taap.2013.09.009
[17] Fricker LD. Proteasome inhibitor drugs[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 457-476. doi:10.1146/annurev-pharmtox-010919-023603
[18] Oliveri V, Lanza V, Milardi D, et al. Amino- and chloro-8-hydroxyquinolines and their copper complexes as proteasome inhibitors and antiproliferative agents[J]. Metallomics, 2017, 9(10): 1439-1446. doi:10.1039/c7mt00156h
[19] Yi M, Jiao D, Qin S, et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment[J]. Mol Cancer, 2019, 18(1): 60. doi:10.1186/s12943-019-0974-6
[20] Baldari S, Di Rocco G, Toietta G. Current biomedical use of copper chelation therapy[J]. Int J Mol Sci, 2020, 21(3): E1069. doi:10.3390/ijms21031069
[21] Czonkowska A, Litwin T, Dusek P, et al. Wilson disease[J]. Nat Rev Dis Primers, 2018, 4(1): 21. doi:10.1038/s41572-018-0018-3
[22] Brewer GJ. Copper-lowering therapy with tetrathiomolybdate for cancer and diseases of fibrosis and inflammation[J]. J Trace Elem Exp Med, 2003, 16(4): 191-199. doi:10.1002/jtra.10045
[23] Chan N, Willis A, Kornhauser N, et al. Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases[J]. Clin Cancer Res, 2017, 23(3): 666-676. doi:10.1158/1078-0432.CCR-16-1326
[24] Morisawa A, Okui T, Shimo T, et al. Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma[J]. Int J Oncol, 2018, 52(3): 989-999. doi:10.3892/ijo.2018.4242
[25] Ryumon S, Okui T, Kunisada Y, et al. Ammonium tetrathiomolybdate enhances the antitumor effect of cisplatin via the suppression of ATPase copper transporting beta in head and neck squamous cell carcinoma[J]. Oncol Rep, 2019, 42(6): 2611-2621. doi:10.3892/or.2019.7367
[26] Yi M, Jiao D, Qin S, et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment[J]. Mol Cancer, 2019, 18(1): 60. doi:10.1186/s12943-019-0974-6
[27] Zhou P, Qin J, Zhou C, et al. Multifunctional nanoparticles based on a polymeric copper Chelator for combination treatment of metastatic breast cancer[J]. Biomaterials, 2019, 195: 86-99. doi:10.1016/j.biomaterials.2019.01.007
[28] Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress[J]. Nat Chem Biol, 2019, 15(7): 681-689. doi:10.1038/s41589-019-0291-9
[29] Cobine PA, Brady DC. Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death[J]. Mol Cell, 2022, 82(10):1786-1787. doi:10.1016/j.molcel.2022.05.001
[30] Kahlson MA, Dixon SJ. Copper-induced cell death[J]. Science, 2022, 375(6586): 1231-1232. doi:10.1126/science.abo3959
[31] Tang D, Chen X, Kroemer G. Cuproptosis: a copper-triggered modality of mitochondrial cell death[J]. Cell Res, 2022, 32(5): 417-418. doi:10.1038/s41422-022-00653-7
[32] 林锦贤, 王攀, 吴欣谋, 等. 铜稳态失调诱导调节性细胞死亡及其调控的研究进展[J]. 江苏大学学报(医学版), 2022, 32(4): 306-317. doi:10.13312/j.issn.1671-7783.y220089 LIN Jinxian, WANG Pan, WU Xinmou, et al. Research progress of regulatory cell death induced by copper homeostasis disorder and its regulation[J]. Journal of Jiangsu University(Medicine Edition), 2022, 32(4): 306-317. doi:10.13312/j.issn.1671-7783.y220089
[33] Cappuccino JG, Banks S, Brown G, et al. The effect of copper and other metal ions on the antitumor activity of pyruvaldehyde bis(thiosemicarbazone)[J]. Cancer Res, 1967, 27(5): 968-973
[34] Singh P, Youden B, Yang YK, et al. Synergistic multimodal cancer therapy using glucose Oxidase@CuS nanocomposites[J]. ACS Appl Mater Interfaces, 2021, 13(35): 41464-41472. doi:10.1021/acsami.1c12235
[35] Michalczyk K, Cymbaluk-Poska A. The role of zinc and copper in gynecological malignancies[J]. Nutrients, 2020,12(12):3732. doi: 10.3390/nu12123732
[36] Blockhuys S, Celauro E, Hildesjö C, et al. Defining the human copper proteome and analysis of its expression variation in cancers[J]. Metallomics, 2017, 9(2): 112-123. doi:10.1039/c6mt00202a
[37] Cui L, Gouw AM, LaGory EL, et al. Mitochondrial copper depletion suppresses triple-negative breast cancer in mice[J]. Nat Biotechnol, 2021, 39(3): 357-367. doi:10.1038/s41587-020-0707-9
[38] Zeng XB, Liu CX, Yao J, et al. Breast cancer stem cells, heterogeneity, targeting therapies and therapeutic implications[J]. Pharmacol Res, 2021, 163: 105320. doi:10.1016/j.phrs.2020.105320
[39] Wang Y, Li W, Patel SS, et al. Blocking the formation of radiation-induced breast cancer stem cells[J]. Oncotarget, 2014, 5(11): 3743-3755. doi:10.18632/oncotarget.1992
[40] Nilsson G, Kannius-Janson M. Forkhead Box F1 promotes breast cancer cell migration by upregulating lysyl oxidase and suppressing Smad2/3 signaling[J]. BMC Cancer, 2016, 16: 142. doi:10.1186/s12885-016-2196-2
[41] Liu YL, Bager CL, Willumsen N, et al. Tetrathiomolybdate(TM)-associated copper depletion influences collagen remodeling and immune response in the pre-metastatic niche of breast cancer[J]. NPJ Breast Cancer, 2021, 7(1): 108. doi:10.1038/s41523-021-00313-w
[42] Liao Y, Zhao J, Bulek K, et al. Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis[J]. Nat Commun, 2020, 11(1): 900. doi:10.1038/s41467-020-14698-y
[43] Aubert L, Nandagopal N, Steinhart Z, et al. Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer[J]. Nat Commun, 2020, 11(1): 3701. doi:10.1038/s41467-020-17549-y
[44] Gao W, Huang Z, Duan J, et al. Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A[J]. Mol Oncol, 2021, 15(12): 3527-3544. doi:10.1002/1878-0261.13079
[45] Xiong K, Zhou Y, Karges J, et al. Autophagy-dependent apoptosis induced by apoferritin-Cu(II)nanoparticles in multidrug-resistant colon cancer cells[J]. ACS Appl Mater Interfaces, 2021, 13(33): 38959-38968. doi:10.1021/acsami.1c07223
[46] Hu YT, Qian YC, Wei JS, et al. The disulfiram/copper complex induces autophagic cell death in colorectal cancer by targeting ULK1[J]. Front Pharmacol, 2021, 12: 752825. doi:10.3389/fphar.2021.752825
[47] Huang X, Hou Y, Weng X, et al. Diethyldithiocarbamate-copper complex(CuET)inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway[J]. Oncogenesis, 2021, 10(1): 4. doi:10.1038/s41389-020-00295-7
[48] Wang WJ, Wang X, Luo JJ, et al. Serum copper level and the copper-to-zinc ratio could be useful in the prediction of lung cancer and its prognosis: a case-control study in northeast China[J]. Nutr Cancer, 2021, 73(10): 1908-1915. doi:10.1080/01635581.2020.1817957
[49] Falls-Hubert KC, Butler AL, Gui K, et al. Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper[J]. Free Radic Biol Med, 2020, 150: 1-11. doi:10.1016/j.freeradbiomed.2020.01.186
[50] Tsang T, Posimo JM, Gudiel AA, et al. Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma[J]. Nat Cell Biol, 2020, 22(4): 412-424. doi:10.1038/s41556-020-0481-4
[51] Kemp MG. Crosstalk between apoptosis and autophagy: environmental genotoxins, infection, and innate immunity[J]. J Cell Death, 2017,9: 1179670716685085. doi:10.1177/1179670716685085
[52] Wu X, Xue X, Wang LH, et al. Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer[J]. Eur J Pharmacol, 2018, 827: 1-12. doi:10.1016/j.ejphar.2018.02.039
[53] Cheng Q, Butler W, Zhou Y, et al. Pre-existing castration-resistant prostate cancer-like cells in primary prostate cancer promote resistance to hormonal therapy[J]. Eur Urol, 2022, 81(5): 446-455. doi:10.1016/j.eururo.2021.12.039
[54] Safi R, Nelson ER, Chitneni SK, et al. Copper signaling axis as a target for prostate cancer therapeutics[J]. Cancer?Res, 2014, 74(20): 5819-5831. doi:10.1158/0008-5472.CAN-13-3527
[55] Zhang T, Kephart J, Bronson E, et al. Prospective clinical trial of disulfiram plus copper in men with metastatic castration-resistant prostate cancer[J]. Prostate, 2022, 82(7): 858-866. doi:10.1002/pros.24329
[56] Bakthavatsalam S, Sleeper ML, Dharani A, et al. Leveraging γ-glutamyl transferase to direct cytotoxicity of copper dithiocarbamates against prostate cancer cells[J]. Angew Chem Int Ed Engl, 2018, 57(39): 12780-12784. doi:10.1002/anie.201807582
[57] Machado JF, Sequeira D, Marques F, et al. New copper(I)complexes selective for prostate cancer cells[J]. Dalton?Trans, 2020, 49(35): 12273-12286. doi:10.1039/d0dt02157a
[58] Voli F, Valli E, Lerra L, et al. Intratumoral copper modulates PD-L1 expression and influences tumor immune evasion[J]. Cancer Res, 2020, 80(19): 4129-4144. doi:10.1158/0008-5472.CAN-20-0471
[1] 马静远, 武天义, 孙占伟, 王卫卫, 李世超, 王广科. 鼻腔鼻窦内翻性乳头状瘤与外周血炎症标志物的相关性研究[J]. 山东大学耳鼻喉眼学报, 2022, 36(4): 35-39.
[2] 韩继波,邹游,杨蕊,陶泽璋. Notch受体调控上皮-间质转化对鼻咽癌细胞顺铂耐药的影响[J]. 山东大学耳鼻喉眼学报, 2020, 34(4): 105-110.
[3] 王莹莹,张立庆,周涵,董诗坤,陈海兵,陈曦,董伟达. 74例鳃裂囊肿及瘘管临床分析[J]. 山东大学耳鼻喉眼学报, 2020, 34(4): 111-116.
[4] 于克娜,孙凯月,张杰,金鹏. 西妥昔单抗治疗头颈部鳞状细胞癌差异表达基因的生物信息学分析[J]. 山东大学耳鼻喉眼学报, 2020, 34(4): 117-124.
[5] 王智立,陈哲,林芳羽,柴永川,汪照炎. 修复治疗不同情形下腮腺区面神经损伤[J]. 山东大学耳鼻喉眼学报, 2020, 34(1): 15-19.
[6] 冯剑,周涵,宋圣花,赵青,张佳程,刘雅琴,沈宇杰,董伟达. 鼻腔鼻窦腺样囊性癌15例临床分析[J]. 山东大学耳鼻喉眼学报, 2019, 33(5): 87-91.
[7] 李林,张衡,冼宇飞,盛晓丽. 长链非编码RNA在鼻咽癌组织中表达及其生物学功能研究[J]. 山东大学耳鼻喉眼学报, 2019, 33(5): 69-72.
[8] 潘晓菲,王军,肖洋,马丽晶. LncRNA CTB-147C22.8对复发性呼吸道乳头状瘤细胞侵袭的影响[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 66-70.
[9] 罗通勇,杨华清,岳胜清,贾全凡,袁龙. 帕尼单抗和紫杉醇一线治疗复发或转移性头颈肿瘤Ⅱ期患者效果观察[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 71-75.
[10] 丁洁,孙彦. 142例喉癌术后患者整体睡眠质量状况调查分析[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 76-81.
[11] 黄河,欧阳晖. 下咽癌共病食管癌的高危因素及预后分析[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 82-86.
[12] 张小平,杨登权,王少新,黄小明. 连续性院外管理对喉癌患者术后生活质量的影响[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 169-174.
[13] 刘鸣. 早期声门癌的内镜治疗[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 6-9.
[14] 孙笑晗,李娜. 喉保留策略在喉癌治疗中的应用—美国临床肿瘤学会临床实践指南更新(2017)介绍[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 40-42.
[15] 黄泽雷,宋琦,路秀英,崔兰珍,李晓明. 双氢青蒿素对下咽癌Fadu细胞内质网应激途径的作用[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 31-35.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!