乙醛脱氢酶2型与乙醛在肿瘤发生发展中的作用
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摘要
乙醛脱氢酶2型(aldehyde dehydrogenase 2 family,ALDH2)是一种线粒体酶,其主要作用是将乙醛(acetaldehyde,ACE)代谢成乙酸,以供后续参与生物体的能量代谢与生物合成。在人群中,ALDH2活性位点存在高频率变异,致使该人群对酒精不耐受,易患急性酒精中毒等饮酒相关疾病。越来越多的证据显示,ALDH2基因的多样性在肿瘤的发生、生长、转移和抗药性中也发挥着重要作用。文章回顾了ALDH2以及其底物ACE在肿瘤研究中的最新进展,阐述了可调控其活性的药物及调控机制,并预测ALDH2可能成为癌症预后的标志物和癌症治疗的新靶点。
Aldehyde dehydrogenase 2(ALDH2) is a mitochondrial enzyme,which catalyzes the oxidation of acetaldehyde to acetic acid for subsequent energy metabolism and biosynthesis. In hu-man,there is a high frequency mutation in the ALDH2 active site,which confers a subpopulation intolerant to alcohol and susceptible to alcohol-related diseases,such as acute alcoholism. Emerging studies suggest that the genetic polymorphism of ALDH2 also plays an important role in tumorigenesis,tumor growth,metastasis,and drug resistance. In this review,the recent advances in cancer research of ALDH2 and acetaldehyde as well as the activity of regulatory drugs and its mechanisms are summerized. It is expected that ALDH2 may be used as a biomarker for cancer prognosis and a new target for cancer therapy.
Aldehyde dehydrogenase 2(ALDH2) is a mitochondrial enzyme,which catalyzes the oxidation of acetaldehyde to acetic acid for subsequent energy metabolism and biosynthesis. In hu-man,there is a high frequency mutation in the ALDH2 active site,which confers a subpopulation intolerant to alcohol and susceptible to alcohol-related diseases,such as acute alcoholism. Emerging studies suggest that the genetic polymorphism of ALDH2 also plays an important role in tumorigenesis,tumor growth,metastasis,and drug resistance. In this review,the recent advances in cancer research of ALDH2 and acetaldehyde as well as the activity of regulatory drugs and its mechanisms are summerized. It is expected that ALDH2 may be used as a biomarker for cancer prognosis and a new target for cancer therapy.
引文
[1]Park JY,Matsuo K,Suzuki T,et al.Impact of smoking on lung cancer risk is stronger in those with the homozygous aldehyde dehydrogenase 2 null allele in a Japanese population[J].Carcinogenesis,2010,31(4):660-665.
[2]Adams KE,Rans TS.Adverse reactions to alcohol and alcoholic beverages[J].Ann Allergy Asthma Immunol,2013,111(6):439-445.
[3]Uebelacker M,Lachenmeier DW.Quantitative determination of acetaldehyde in foods using automated digestion with simulated gastric fluid followed by headspace gas chromatography[J].J Anal Methods Chem,2011,2011:907317.
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[6]Seitz HK,Stickel F.Acetaldehyde as an underestimated risk factor for cancer development:role of genetics in ethanol metabolism[J].Genes Nutr,2010,5(2):121-128.
[7]Chen X,Legrand AJ,Cunniffe S,et al.Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients[J].Cell Oncol,2018,41(5):527-539.
[8]Eom SY,Zhang YW,Kim SH,et al.Influence of NQO1,ALDH2,and CYP2E1 genetic polymorphisms,smoking,and alcohol drinking on the risk of lung cancer in Koreans[J].Cancer Causes Control,2009,20(2):137-145.
[9]Singh R,Sandhu J,Kaur B,et al.Evaluation of the DNAdamaging potential of cannabis cigarette smoke by the determination of acetaldehyde derived N2-ethyl-2'-deoxyguanosine adducts[J].Chem Res Toxicol,2009,22(6):1181-1188.
[10]Upton DC,Wang X,Blans P,et al.Replication of N2-ethyldeoxyguanosine DNA adducts in the human embryonic kidney cell line 293[J].Chem Res Toxicol,2006,19(7):960-967.
[11]Brooks PJ,Zakhari S.Acetaldehyde and the genome:beyond nuclear DNA adducts and carcinogenesis[J].Environ Mol Mutagen,2014,55(2):77-91.
[12]Garaycoechea JI,Crossan GP,Langevin F,et al.Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells[J].Nature,2018,553(7687):171-177.
[13]Brooks PJ,Theruvathu JA.DNA adducts from acetaldehyde:implications for alcohol-related carcinogenesis[J].Alcohol,2005,35(3):187-193.
[14]Wang Y,Ichiba M,Iyadomi M,et al.Effects of genetic polymorphism of metabolic enzymes,nutrition,and lifestyle factors on DNA adduct formation in lymphocytes[J].Ind Health,1998,36(4):337-346.
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[29]Hou G,Chen L,Liu G,et al.Aldehyde dehydrogenase-2(ALDH2)opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice[J].Hepatology,2017,65(5):1628-1644.
[30]Elamin E,Masclee A,Troost F,et al.Activation of the epithelial-to-mesenchymal transition factor snail mediates acetaldehyde-induced intestinal epithelial barrier disruption[J].Alcohol Clin Exp Res,2014,38(2):344-353.
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[34]Wang NN,Wang LH,Li Y,et al.Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors[J].Exp Cell Res,2018,362(1):72-82.
[35]Gao YH,Wu ZX,Xie LQ,et al.VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2[J].Nat Commun,2017,8:15337.
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[38]Dalla PE,Donadelli M,Costanzo C,et al.Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives[J].Free Radic Biol Med,2011,50(8):926-933.
[39]Xu B,Shi P,Fombon IS,et al.Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells[J].Blood Cells Mol Dis,2011,47(4):264-269.
[40]Tisato F,Marzano C,Porchia M,et al.Copper in diseases and treatments,and copper-based anticancer strategies[J].Med Res Rev,2010,30(4):708-749.
[41]Liu P,Brown S,Goktug T,et al.Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells[J].Br J Cancer,2012,107(9):1488-1497.
[42]Iljin K,Ketola K,Vainio P,et al.High-throughput cellbased screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth[J].Clin Cancer Res,2009,15(19):6070-6078.
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[44]Wickstr觟m M,Danielsson K,Rickardson L,et al.Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients[J].Biochem Pharmacol,2007,73(1):25-33.
[45]Conticello C,Martinetti D,Adamo L,et al.Disulfiram,an old drug with new potential therapeutic uses for human hematological malignancies[J].Int J Cancer,2012,131(9):2197-2203.
[46]Shian SG,Kao YR,Wu FY,et al.Inhibition of invasion and angiogenesis by Zinc-chelating agent disulfiram[J].Mol Pharmacol,2003,64(5):1076-1084.
[47]Cheriyan VT,Wang Y,Muthu M,et al.Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis[J].PLoS One,2014,9(4):e93711.
[48]Hothi P,Martins TJ,Chen L,et al.High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells[J].Oncotarget,2012,3(10):1124-1136.
[49]Duan X,Xiao J,Yin Q,et al.Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram[J].Nanotechnology,2014,25(12):125102.
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[51]Yip NC,Fombon IS,Liu P,et al.Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties[J].Br JCancer,2011,104(10):1564-1574.
[52]Zhang H,Chen D,Ringler J,et al.Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo[J].Cancer Res,2010,70(10):3996-4004.
[53]Skrott Z,Mistrik M,Andersen KK,et al.Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4[J].Nature,2017,552(7684):194-199.
[54]Johansson B.A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites[J].Acta Psychiatr Scand,1992,369:15-26.
[55]Zhang L,Tian B,Li Y.A copper-mediated disulfiramloaded pH-triggered PEG-shedding TAT peptide-modified lipid nanocapsules for use in tumor therapy[J].ACS Appl Mater Interfaces,2015,7(45):25147-25161.
[56]Sun L,Ferreira JC,Mochly RD.ALDH2 activator inhibits increased myocardial infarction injury by nitroglycerin tolerance[J].Sci Transl Med,2011,3(107):107-111.
[57]Perez MS,Younus H,Vanam R,et al.Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant[J].Nat Struct Mol Biol,2010,17(2):159-164.
[58]Zhang Y,Talalay P,Cho CG,et al.A major inducer of anticarcinogenic protective enzymes from broccoli:isolation and elucidation of structure[J].Proc Natl Acad Sci U S A,1992,89(6):2399-2403.
[59]Ushida Y,Talalay P.Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases:relevance to ethanol intolerance[J].Alcohol,2013,48(5):526-534.
[60]Stefanson AL,Bakovic M.Dietary regulation of Keap1/Nrf2/ARE pathway:focus on plant-derived compounds and trace minerals[J].Nutrients,2014,6(9):3777-3801.
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[62]Cho HY,Reddy SP,Debiase A,et al.Gene expression profiling of NRF2-mediated protection against oxidative injury[J].Free Radic Biol Med,2005,38(3):325-343.
[63]Lampe JW.Sulforaphane:from chemoprevention to pancreatic cancer treatment?[J].Gut,2009,58(7):900-902.
[64]Burnett JP,Lim G,Li Y,et al.Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells[J].Cancer Lett,2017,394:52-64.
[65]Shi YH,Dai DF,Li J,et al.Sulforaphane analogues with heterocyclic moieties:syntheses and inhibitory activities against cancer cell lines[J].Molecules,2016,21(4):514.
[2]Adams KE,Rans TS.Adverse reactions to alcohol and alcoholic beverages[J].Ann Allergy Asthma Immunol,2013,111(6):439-445.
[3]Uebelacker M,Lachenmeier DW.Quantitative determination of acetaldehyde in foods using automated digestion with simulated gastric fluid followed by headspace gas chromatography[J].J Anal Methods Chem,2011,2011:907317.
[4]O'Brien PJ,Siraki AG,Shangari N,et al.Aldehyde sources,metabolism,molecular toxicity mechanisms,and possible effects on human health[J].Crit Rev Toxicol,2005,35(7):609-662.
[5]Jiang Y,Zhang J,Wu Y,et al.Association between ALDH2 rs671 G>A polymorphism and gastric cancer susceptibility in Eastern Asia[J].Oncotarget,2017,8(60):102401-102412.
[6]Seitz HK,Stickel F.Acetaldehyde as an underestimated risk factor for cancer development:role of genetics in ethanol metabolism[J].Genes Nutr,2010,5(2):121-128.
[7]Chen X,Legrand AJ,Cunniffe S,et al.Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients[J].Cell Oncol,2018,41(5):527-539.
[8]Eom SY,Zhang YW,Kim SH,et al.Influence of NQO1,ALDH2,and CYP2E1 genetic polymorphisms,smoking,and alcohol drinking on the risk of lung cancer in Koreans[J].Cancer Causes Control,2009,20(2):137-145.
[9]Singh R,Sandhu J,Kaur B,et al.Evaluation of the DNAdamaging potential of cannabis cigarette smoke by the determination of acetaldehyde derived N2-ethyl-2'-deoxyguanosine adducts[J].Chem Res Toxicol,2009,22(6):1181-1188.
[10]Upton DC,Wang X,Blans P,et al.Replication of N2-ethyldeoxyguanosine DNA adducts in the human embryonic kidney cell line 293[J].Chem Res Toxicol,2006,19(7):960-967.
[11]Brooks PJ,Zakhari S.Acetaldehyde and the genome:beyond nuclear DNA adducts and carcinogenesis[J].Environ Mol Mutagen,2014,55(2):77-91.
[12]Garaycoechea JI,Crossan GP,Langevin F,et al.Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells[J].Nature,2018,553(7687):171-177.
[13]Brooks PJ,Theruvathu JA.DNA adducts from acetaldehyde:implications for alcohol-related carcinogenesis[J].Alcohol,2005,35(3):187-193.
[14]Wang Y,Ichiba M,Iyadomi M,et al.Effects of genetic polymorphism of metabolic enzymes,nutrition,and lifestyle factors on DNA adduct formation in lymphocytes[J].Ind Health,1998,36(4):337-346.
[15]Singh NP,Khan A.Acetaldehyde:genotoxicity and cytotoxicity in human lymphocytes[J].Mutat Res,1995,337(1):9-17.
[16]Noori P,Hou SM.Mutational spectrum induced by acetaldehyde in the HPRT gene of human T lymphocytes resembles that in the p53 gene of esophageal cancers[J].Carcinogenesis,2001,22(11):1825-1830.
[17]Obe G,Jonas R,Schmidt S.Metabolism of ethanol in vitro produces a compound which induces sister-chromatid exchanges in human peripheral lymphocytes in vitro:acetaldehyde not ethanol is mutagenic[J].Mutat Res,1986,174(1):47-51.
[18]Kayani MA,Parry JM.The in vitro genotoxicity of ethanol and acetaldehyde[J].Toxicol In Vitro,2010,24(1):56-60.
[19]Matsuda T,Kawanishi M,Yagi T,et al.Specific tandem GG to TT base substitutions induced by acetaldehyde are due to intra-strand crosslinks between adjacent guanine bases[J].Nucleic Acids Res,1998,26(7):1769-1774.
[20]Seitz HK,Stickel F.Molecular mechanisms of alcohol-mediated carcinogenesis[J].Nat Rev Cancer,2007,7(8):599-612.
[21]Seitz HK,Mueller S.Alcohol and cancer:an overview with special emphasis on the role of acetaldehyde and cytochrome P450 2E1[J].Adv Exp Med Biol,2015,815:59-70.
[22]Yan T,Zhao Y,Zhang X,et al.Astaxanthin inhibits acetaldehyde-induced cytotoxicity in SH-SY5Y cells by modulating Akt/CREB and p38MAPK/ERK signaling pathways[J].Mar Drugs,2016,14(3):56.
[23]Yan T,Zhao Y,Zhang X.Acetaldehyde induces cytotoxicity of SH-SY5Y cells via inhibition of Akt activation and induction of oxidative stress[J].Oxid Med Cell Longev,2016,2016:4512309.
[24]Ming T,Lisa L,Quynh GN,et al.Acetaldehyde-mediated neurotoxicity:relevance to fetal alcohol spectrum disorders[J].Oxid Med Cell Longev,2011,2011(4):213286.
[25]Jung TW,Lee JY,Shim WS,et al.Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity[J].Biochem Biophys Res Commun,2006,72(5):616-623.
[26]Clavijo CD,Gutiérrez CM,Palestino DM.Acetaldehyde targets superoxide dismutase 2 in liver cancer cells inducing transient enzyme impairment and a rapid transcriptional recovery[J].Food Chem Toxicol,2014,69:102-108.
[27]Wenzel P,Müller J,Zurmeyer S,et al.ALDH-2 deficiency increases cardiovascular oxidative stress-evidence for indirect antioxidative properties[J].Biochem Biophys Res Commun,2008,367(1):137-143.
[28]Ohta S,Ohsawa I,Kamino K,et al.Mitochondrial ALDH2deficiency as an oxidative stress[J].Ann N Y Acad Sci,2004,1011:36-44.
[29]Hou G,Chen L,Liu G,et al.Aldehyde dehydrogenase-2(ALDH2)opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice[J].Hepatology,2017,65(5):1628-1644.
[30]Elamin E,Masclee A,Troost F,et al.Activation of the epithelial-to-mesenchymal transition factor snail mediates acetaldehyde-induced intestinal epithelial barrier disruption[J].Alcohol Clin Exp Res,2014,38(2):344-353.
[31]Xue L,Yang F,Han Z,et al.ALDH2 mediates the doseresponse protection of chronic ethanol against endothelial senescence through SIRT1/p53 pathway[J].Biochem Biophys Res Commun,2018,504(4):777-783.
[32]Moreb JS,Ucar D,Han S,et al.The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2(ALDH1A2and ALDH2)is detected by Aldefluor,inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance[J].Chem Biol Interact,2012,195(1):52-60.
[33]Kim J,Chen CH,Yang J,et al.Aldehyde dehydrogenase2*2 knock-in mice show increased reactive oxygen species production in response to cisplatin treatment[J].J Biomed Sci,2017,24(1):33.
[34]Wang NN,Wang LH,Li Y,et al.Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors[J].Exp Cell Res,2018,362(1):72-82.
[35]Gao YH,Wu ZX,Xie LQ,et al.VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2[J].Nat Commun,2017,8:15337.
[36]Liu P,Kumar IS,Brown S,et al.Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells[J].Br J Cancer,2013,109(7):1876-1885.
[37]Lun X,Wells JC,Grinshtein N,et al.Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma[J].Clin Cancer Res,2016,22(15):3860-3875.
[38]Dalla PE,Donadelli M,Costanzo C,et al.Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives[J].Free Radic Biol Med,2011,50(8):926-933.
[39]Xu B,Shi P,Fombon IS,et al.Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells[J].Blood Cells Mol Dis,2011,47(4):264-269.
[40]Tisato F,Marzano C,Porchia M,et al.Copper in diseases and treatments,and copper-based anticancer strategies[J].Med Res Rev,2010,30(4):708-749.
[41]Liu P,Brown S,Goktug T,et al.Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells[J].Br J Cancer,2012,107(9):1488-1497.
[42]Iljin K,Ketola K,Vainio P,et al.High-throughput cellbased screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth[J].Clin Cancer Res,2009,15(19):6070-6078.
[43]Cvek B.Nonprofit drugs as the salvation of the world’s healthcare systems:the case of Antabuse(disulfiram)[J].Drug Discov Today,2012,17(9-10):409-412.
[44]Wickstr觟m M,Danielsson K,Rickardson L,et al.Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients[J].Biochem Pharmacol,2007,73(1):25-33.
[45]Conticello C,Martinetti D,Adamo L,et al.Disulfiram,an old drug with new potential therapeutic uses for human hematological malignancies[J].Int J Cancer,2012,131(9):2197-2203.
[46]Shian SG,Kao YR,Wu FY,et al.Inhibition of invasion and angiogenesis by Zinc-chelating agent disulfiram[J].Mol Pharmacol,2003,64(5):1076-1084.
[47]Cheriyan VT,Wang Y,Muthu M,et al.Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis[J].PLoS One,2014,9(4):e93711.
[48]Hothi P,Martins TJ,Chen L,et al.High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells[J].Oncotarget,2012,3(10):1124-1136.
[49]Duan X,Xiao J,Yin Q,et al.Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram[J].Nanotechnology,2014,25(12):125102.
[50]Wang F,Zhai S,Liu X,et al.A novel dithiocarbamate analogue with potentially decreased ALDH inhibition has copper-dependent proteasome-inhibitory and apoptosis-inducing activity in human breast cancer cells[J].Cancer Lett,2011,300(1):87-95.
[51]Yip NC,Fombon IS,Liu P,et al.Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties[J].Br JCancer,2011,104(10):1564-1574.
[52]Zhang H,Chen D,Ringler J,et al.Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo[J].Cancer Res,2010,70(10):3996-4004.
[53]Skrott Z,Mistrik M,Andersen KK,et al.Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4[J].Nature,2017,552(7684):194-199.
[54]Johansson B.A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites[J].Acta Psychiatr Scand,1992,369:15-26.
[55]Zhang L,Tian B,Li Y.A copper-mediated disulfiramloaded pH-triggered PEG-shedding TAT peptide-modified lipid nanocapsules for use in tumor therapy[J].ACS Appl Mater Interfaces,2015,7(45):25147-25161.
[56]Sun L,Ferreira JC,Mochly RD.ALDH2 activator inhibits increased myocardial infarction injury by nitroglycerin tolerance[J].Sci Transl Med,2011,3(107):107-111.
[57]Perez MS,Younus H,Vanam R,et al.Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant[J].Nat Struct Mol Biol,2010,17(2):159-164.
[58]Zhang Y,Talalay P,Cho CG,et al.A major inducer of anticarcinogenic protective enzymes from broccoli:isolation and elucidation of structure[J].Proc Natl Acad Sci U S A,1992,89(6):2399-2403.
[59]Ushida Y,Talalay P.Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases:relevance to ethanol intolerance[J].Alcohol,2013,48(5):526-534.
[60]Stefanson AL,Bakovic M.Dietary regulation of Keap1/Nrf2/ARE pathway:focus on plant-derived compounds and trace minerals[J].Nutrients,2014,6(9):3777-3801.
[61]Lee JM,Calkins MJ,Chan K,et al.Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis[J].J Biol Chem,2003,278(14):12029-12038.
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