Disulfiram như một tác nhân điều trị cho Melanoma ác tính di căn—Huyền thoại cũ hay biểu tượng mới?
Tóm tắt
Các khái niệm liệu pháp mới như liệu pháp miễn dịch dựa trên anti-PD-1 hoặc liệu pháp nhắm mục tiêu với các chất ức chế BRAF và MEK đã cải thiện đáng kể tỷ lệ sống sót cho bệnh nhân melanoma. Tuy nhiên, khoảng 20% bệnh nhân điều trị nhắm mục tiêu và lên tới 50% bệnh nhân điều trị miễn dịch không đáp ứng với liệu pháp điều trị đầu tay của họ hoặc nhanh chóng phát triển kháng thuốc. Hơn nữa, hiện tại không có liệu pháp nhắm mục tiêu nào được phê duyệt cho một số tiểu nhóm nhất định, chẳng hạn như melanoma kiểu hoang dã BRAF, mặc dù chúng thường mang sinh học khối u hung hãn. Việc tái sử dụng các loại thuốc đã được phê duyệt trước đây là một chiến lược đầy hứa hẹn để lấp đầy khoảng trống này, vì nó sẽ dẫn đến chi phí tương đối thấp, giảm rủi ro và tiết kiệm thời gian. Disulfiram (DSF), loại thuốc đầu tiên dùng để điều trị nghiện rượu, được Cục Quản lý Thực phẩm và Dược phẩm Hoa Kỳ phê duyệt hơn 60 năm trước, là một ứng viên thuốc như vậy. Có ngày càng nhiều bằng chứng cho thấy DSF có tiềm năng lớn trong việc điều trị nhiều loại ung thư ở người, bao gồm melanoma. Một số cơ chế hoạt động chống khối u của nó đã được xác định, trong đó có việc ức chế hệ thống ubiquitin-proteasome, kích thích các gốc oxy phản ứng và nhiều con đường tín hiệu chết khác nhau. Bài báo này cung cấp cái nhìn tổng quan về việc áp dụng DSF ở người, các cơ chế phân tử và các mục tiêu trong liệu pháp ung thư với trọng tâm là melanoma. Kết quả của các nghiên cứu lâm sàng và các phương pháp kết hợp thử nghiệm giữa DSF với các liệu pháp ung thư khác nhau sẽ được thảo luận, với mục tiêu khám phá tiềm năng của DSF trong liệu pháp điều trị melanoma.
Từ khóa
Tài liệu tham khảo
Grodzki, 1881, Ueber äthylirte Sulfoharnstoffe, Eur. J. Inorg. Chem., 14, 2754
Twiss, 1922, The Dithiocarbamate Accelerators of Vulcanization, J. Soc. Chem. Ind., 41, 81
Kragh, 2008, From Disulfiram to Antabuse: The Invention of a Drug, Bull. Hist. Chem., 33, 82
(2009). Treatment Improvement Protocol (TIP) Series, No. 49. Incorporating Alcohol Pharmacotherapies into Medical Practice.
Hald, 2009, The Formation of Acetaldehyde in the Organism after Ingestion of Antabuse (Tetraethylthiuram disulphide) and Alcohol, Acta Pharmacol. Toxicol., 4, 305, 10.1111/j.1600-0773.1948.tb03352.x
The Mark Collection (2012). Disulfiram [Mak Value Documentation, 1993]. The Mak—Collection for Occupational Health and Safety: Annual Thresholds and Classifications for the Workplace, Wiley-VCH Verlag GmbH & Co. KGaA.
Mattei, 1986, Induction of Stress Proteins in Murine and Human Melanoma Cell Cultures, Tumori J., 72, 129, 10.1177/030089168607200202
Skrott, 2017, Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4, Nat. Cell Biol., 552, 194
Li, 2020, The combination of disulfiram and copper for cancer treatment, Drug Discov. Today, 25, 1099, 10.1016/j.drudis.2020.04.003
Information, National Center for Biotechnology (2020, October 01). Pubchem Compound Summary for Cid 3117, Disulfiram, Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Disulfiram.
Johansson, 1992, A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites, Acta Psychiatr. Scand., 86, 15, 10.1111/j.1600-0447.1992.tb03310.x
Kardos, 2018, Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited, Bioorg. Med. Chem. Lett., 28, 3113, 10.1016/j.bmcl.2018.07.001
Petersen, 1992, The pharmacology and toxicology of disulfiram and its metabolites, Acta Psychiatr. Scand., 86, 7, 10.1111/j.1600-0447.1992.tb03309.x
Askgaard, 2014, Use of disulfiram and risk of cancer, Eur. J. Cancer Prev., 23, 225, 10.1097/CEJ.0b013e3283647466
Li, Y., Chen, F., Chen, J., Chan, S., He, Y., Liu, W., and Zhang, G. (2020). Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways. Cancers, 12.
Cvek, 2008, The Value of Proteasome Inhibition in Cancer. Can the Old Drug, Disulfiram, Have a Bright New Future as a Novel Proteasome Inhibitor?, Drug Discov. Today, 13, 716, 10.1016/j.drudis.2008.05.003
Morrison, 2010, Disulfiram induces copper-dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic pathway in melanoma, Melanoma Res., 20, 11, 10.1097/CMR.0b013e328334131d
Rieber, 2015, Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: Antagonism by tetrathiomolybdate, Oncotarget, 6, 29771, 10.18632/oncotarget.4833
Nobel, 1997, Mechanism of Dithiocarbamate Inhibition of Apoptosis: Thiol Oxidation by Dithiocarbamate Disulfides Directly Inhibits Processing of the Caspase-3 Proenzyme, Chem. Res. Toxicol., 10, 636, 10.1021/tx970006a
Fruehauf, 2008, Reactive oxygen species: An Achilles’ heel of melanoma?, Expert Rev. Anticancer. Ther., 8, 1751, 10.1586/14737140.8.11.1751
Brar, 2004, Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease, Mol. Cancer Ther., 3, 1049, 10.1158/1535-7163.1049.3.9
Cen, 2004, Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells, J. Med. Chem., 47, 6914, 10.1021/jm049568z
Trapp, 2009, Redox-related antimelanoma activity of ATN-224, Melanoma Res., 19, 350, 10.1097/CMR.0b013e32832c6324
Cen, 2002, Disulfiram induces apoptosis in human melanoma cells: A redox-related process, Mol. Cancer Ther., 1, 197
Balakirev, 2001, Mitochondrial injury by disulfiram: Two different mechanisms of the mitochondrial permeability transition, Chem. Interact., 138, 299, 10.1016/S0009-2797(01)00283-6
Xu, 2020, Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways, Biomed. Pharmacother., 126, 110048, 10.1016/j.biopha.2020.110048
Xu, 2011, Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells, Blood Cells Mol. Dis., 47, 264, 10.1016/j.bcmd.2011.08.004
Kamata, 2005, Reactive Oxygen Species Promote Tnfalpha-Induced Death and Sustained Jnk Activation by Inhibiting Map Kinase Phosphatases, Cell, 120, 649, 10.1016/j.cell.2004.12.041
Shi, 2014, ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis, Cell Death Differ., 21, 612, 10.1038/cdd.2013.186
Hu, 2020, FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation, Nat. Immunol., 21, 736, 10.1038/s41590-020-0669-6
Henkel, 1993, Rapid Proteolysis of I Kappa B-Alpha Is Necessary for Activation of Transcription Factor Nf-κB, Nature, 365, 182, 10.1038/365182a0
Annunziata, 2007, Frequent Engagement of the Classical and Alternative Nf-Kappab Pathways by Diverse Genetic Abnormalities in Multiple Myeloma, Cancer Cell, 12, 115, 10.1016/j.ccr.2007.07.004
Pham, 2007, Upregulation of Twist-1 by NF-κB Blocks Cytotoxicity Induced by Chemotherapeutic Drugs, Mol. Cell. Biol., 27, 3920, 10.1128/MCB.01219-06
Di, 2005, Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis, Front. Biosci., 10, 2932, 10.2741/1749
Daniel, 2005, Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells, Breast Cancer Res., 7, R897, 10.1186/bcr1322
Kim, 2004, Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis, Exp. Cell Res., 298, 229, 10.1016/j.yexcr.2004.04.017
Farmer, 2003, Melanin as a Target for Melanoma Chemotherapy: Pro-oxidant Effect of Oxygen and Metals on Melanoma Viability, Pigment. Cell Res., 16, 273, 10.1034/j.1600-0749.2003.00046.x
Majera, D., Skrott, Z., Chroma, K., Merchut-Maya, J.M., Mistrik, M., and Bartek, J. (2020). Targeting the Npl4 Adaptor of P97/Vcp Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage While Silencing the Atr Pathway. Cells, 9.
Brar, 2001, Reactive oxygen species from NAD(P)H:quinone oxidoreductase constitutively activate NF-κb in malignant melanoma cells, Am. J. Physiol. Physiol., 280, 659, 10.1152/ajpcell.2001.280.3.C659
Meyskens, 1999, Activation of nuclear factor-kappa B in human metastatic melanomacells and the effect of oxidative stress, Clin. Cancer Res., 5, 1197
Yakisich, 2001, Disulfiram Is a Potent In Vitro Inhibitor of DNA Topoisomerases, Biochem. Biophys. Res. Commun., 289, 586, 10.1006/bbrc.2001.6027
Shian, 2003, Inhibition of Invasion and Angiogenesis by Zinc-Chelating Agent Disulfiram, Mol. Pharmacol., 64, 1076, 10.1124/mol.64.5.1076
Grossmann, 2011, Abstract 1308: A phase I clinical study investigating disulfiram and copper gluconate in patients with advanced treatment-refractory solid tumors involving the liver, Clin. Trials, 71, 1308
Schweizer, 2013, Pharmacodynamic Study of Disulfiram in Men with Non-Metastatic Recurrent Prostate Cancer, Prostate Cancer Prostatic Dis., 16, 357, 10.1038/pcan.2013.28
Nechushtan, 2015, A Phase IIb Trial Assessing the Addition of Disulfiram to Chemotherapy for the Treatment of Metastatic Non-Small Cell Lung Cancer, Oncology, 20, 366
Zhang, 2020, Disulfiram (DSF) pharmacokinetics (PK) and copper PET imaging in a phase Ib study of intravenous (IV) copper loading with oral DSF for patients with metastatic castration-resistant prostate cancer (mCRPC), J. Clin. Oncol., 38, 96, 10.1200/JCO.2020.38.6_suppl.96
Grossmann, K.F., Terrazas, M., Khong, H.T., Akerley, W., Kosak, K., Boucher, K., Kennedy, T.P., and Shami, P.J. (2013). Abstract LB-175: Phase II study of disulfiram and chelated Zn for the treatment of disseminated metastatic melanoma. Clin. Trials, 73.
Huang, 2018, Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma, J. Neuro-Oncol., 138, 105, 10.1007/s11060-018-2775-y
Huang, 2019, A TITE-CRM Phase I/II Study of Disulfiram and Copper with Concurrent Radiation Therapy and Temozolomide for Newly Diagnosed Glioblastoma, J. Clin. Oncol., 37, 2033, 10.1200/JCO.2019.37.15_suppl.2033
Huang, 2019, A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma, J. Neuro-Oncol., 142, 537, 10.1007/s11060-019-03125-y
Koh, 2018, Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro, Cancer Res. Treat., 51, 696, 10.4143/crt.2018.249
Rae, 2013, The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells, J. Nucl. Med., 54, 953, 10.2967/jnumed.112.113324
Wang, 2003, Disulfiram-Mediated Inhibition of Nf-Kappab Activity Enhances Cytotoxicity of 5-Fluorouracil in Human Colorectal Cancer Cell Lines, Int. J. Cancer, 104, 504, 10.1002/ijc.10972
Huang, 2016, Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo, Oncotarget, 7, 2796, 10.18632/oncotarget.6425
Zhao, 2018, Dual-Targeting Biomimetic Delivery for Anti-Glioma Activity Via Remodeling the Tumor Microenvironment and Directing Macrophage-Mediated Immunotherapy, Chem. Sci., 9, 2674, 10.1039/C7SC04853J
Triscott, 2012, Disulfiram, a Drug Widely Used to Control Alcoholism, Suppresses the Self-Renewal of Glioblastoma and over-Rides Resistance to Temozolomide, Oncotarget, 3, 1112, 10.18632/oncotarget.604
Cornejo, 2019, Anticancer response to disulfiram may be enhanced by co-treatment with MEK inhibitor or oxaliplatin: Modulation by tetrathiomolybdate, KRAS/BRAF mutations and c-MYC/p53 status, Ecancermedicalscience, 13, 890
Paranjpe, 2013, Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage, Carcinogenesis, 35, 692, 10.1093/carcin/bgt366
Bodenner, 1986, Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate, Cancer Res., 46, 2751
Loo, 2000, Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism, J. Natl. Cancer Inst., 92, 898, 10.1093/jnci/92.11.898
Brady, 2014, Copper is required for oncogenic BRAF signalling and tumorigenesis, Nat. Cell Biol., 509, 492
Sammons, 2016, Copper suppression as cancer therapy: The rationale for copper chelating agents inBRAFV600mutated melanoma, Melanoma Manag., 3, 207, 10.2217/mmt-2015-0005
Turski, 2012, A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling, Mol. Cell. Biol., 32, 1284, 10.1128/MCB.05722-11
Jones, 2016, Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics, Oncotarget, 7, 40348, 10.18632/oncotarget.9613