Identification of a novel cytosolic aldehyde dehydrogenase allele, ALDH1A1*4.
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ABSTRACT:
SUBMITTER: Moore SM
PROVIDER: S-EPMC2885287 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDH1A1) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.
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Project description:BackgroundCisplatin is the standard first-line chemotherapeutic agent for the treatment of non-small cell lung cancer (NSCLC). However, resistance to chemotherapy has been a major obstacle in the management of NSCLC. Aldehyde dehydrogenase 1A1 (ALDH1A1) overexpression has been observed in a variety of cancers, including lung cancer. The purpose of this study was to investigate the effect of ALDH1A1 expression on cisplatin resistance and explore the mechanism responsible.MethodsReverse transcriptase-PCR was applied to measure the messenger RNA expression of ALDH1A1, while Western blot assay was employed to evaluate the protein expression of ALDH1A1, B-cell lymphoma 2, Bcl-2-like protein 4, phospho-protein kinase B (p-AKT) and AKT. A short hairpin RNA was used to knockdown ALDH1A1 expression. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the effect of ALDH1A1 decrease on cell viability. The cell apoptotic rate was tested using flow cytometry assay.ResultsALDH1A1 is overexpressed in cisplatin resistant cell line A549/DDP, compared with A549. ALDH1A1 depletion significantly decreased A549/DDP proliferation, increased apoptosis, and reduced cisplatin resistance. In addition, the phosphoinositide 3-kinase (PI3K) / AKT pathway is activated in A549/DDP, and ALDH1A1 knockdown reduced the phosphorylation level of AKT. Moreover, the combination of ALDH1A1-short hairpin RNA and PI3K/AKT pathway inhibitor LY294002 markedly inhibited cell viability, enhanced apoptotic cell death, and increased cisplatin sensitivity.ConclusionThese results suggest that ALDH1A1 depletion could reverse cisplatin resistance in human lung cancer cell line A549/DDP, and may act as a potential target for the treatment of lung cancers resistant to cisplatin.
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Project description:Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17?4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.
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Project description:Liver cystolic aldehyde dehydrogenase 1 (ALDH1A1) has been previously associated with both alcohol dependence and alcohol consumption behaviour, and has been implicated in alcohol-induced flushing and alcohol sensitivity in Caucasians. The present study tested for association between ALDH1A1 and alcohol consumption behaviour and susceptibility to problem drinking or alcohol dependence in Finnish cohorts of unrelated male subjects recruited from alcoholism clinical treatment facilities ( n = 104) and from the general population ( n = 201). All participants completed the Alcohol Use Disorder Identification Test (AUDIT) and were genotyped for eight single nucleotide polymorphisms (SNPs) within or flanking ALDH1A1 . To test for association between alcohol consumption behaviour and these polymorphisms, we used generalised linear models and haplotypic analysis. Three SNPs were nominally associated (rs348449, p = 0.043; rs610529, p = 0.013; rs348479, p = 0.025) with the quantitative AUDIT score, which evaluates alcohol consumption behaviour. Two-locus (rs610529-rs2288087) haplotype analysis increased the strength of association with AUDIT score ( p = 0.0015). Additionally, rs348449 is highly associated with problem drinking (allelic odds ratio [OR] 7.87, 95 per cent confidence interval [CI] 1.67-37.01) but due to the low minor allele frequency (0.01 and 0.07 in controls and problem drinkers, respectively), more samples are required to validate this observation. Conversely, rs348479 ( p = 0.019) and rs610529 (allelic OR 0.65, 95 per cent CI 0.43-0.98; genotypic OR 0.32, 95 per cent CI 0.12-0.84) are implicated in alcohol dependence status. This study provides further evidence for a role for ALDH1A1 in alcohol consumption behaviour, including problem drinking and possibly alcohol dependence, in our Finnish population.
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Project description:Aldehyde dehydrogenase (ALDH) isozymes are critically important in the metabolism of acetaldehyde, thus preventing its accumulation after ethanol-exposure. We previously reported that mitochondrial ALDH2 could be inactivated via S-nitrosylation in ethanol-exposed rats. This study was aimed at investigating whether cytosolic ALDH1, with a relatively-low-Km value (11-18 microM) for acetaldehyde, could be also inhibited in ethanol-exposed rats. Chronic or binge ethanol-exposure significantly decreased ALDH1 activity, which was restored by addition of dithiothreitol. Immunoblot analysis with the anti-S-nitroso-Cys antibody showed one immunoreactive band in the immunoprecipitated ALDH1 only from ethanol-exposed rats, but not from pair-fed controls, suggesting S-nitrosylation of ALDH1. Therefore inactivation of ALDH1 via S-nitrosylation can result in accumulation of acetaldehyde upon ethanol-exposure.
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Project description:Over the past three years we have been involved in high-throughput screening in an effort to discover novel small molecular modulators of aldehyde dehydrogenase (ALDH) activity. In particular, we have been interested in both the activation and inhibition of the three commonly studied isoenzymes, ALDH1A1, ALDH2 and ALDH3A1, as their distinct, yet overlapping substrate specificities, present a particularly difficult challenge for inhibitor discovery and design. Activation of ALDH2 has been shown to benefit cardiovascular outcome following periods of ischemia and renewed interest in specific inhibition of ALDH2 has application for alcohol aversion therapy, and more recently, in cocaine addiction. In contrast, inhibition of either ALDH1A1 or ALDH3A1 has application in cancer treatments where the isoenzymes are commonly over-expressed and serve as markers for cancer stem cells. We are taking two distinct approaches for these screens: in vitro enzyme activity screens using chemical libraries and virtual computational screens using the structures of the target enzymes as filters for identifying potential inhibitors, followed by in vitro testing of their ability to inhibit their intended targets. We have identified selective inhibitors of each of these three isoenzymes with inhibition constants in the high nanomolar to low micromolar range from these screening procedures. Together, these inhibitors provide proof for concept that selective inhibition of these broad specificity general detoxication enzymes through small molecule discovery and design is possible.
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Project description:BackgroundAldehyde dehydrogenase (ALDH) 1A1 is an immunohistological biomarker of various solid tumours, but has not been successfully proved as a colorectal cancer (CRC) marker. We recently reported that ALDH1B1, which has functional roles in tumourigenesis, may be a better CRC marker than ALDH1A1.MethodsHuman CRC explants and cell lines were analysed to identify candidate CRC markers from eight ALDH isozymes including ALDH1A1 and ALDH1B1. A tissue microarray, including paired specimens of normal and tumour tissues, was subsequently analysed to determine if candidate ALDHs could distinguish CRC from normal tissue.ResultsBased on mRNA analysis, ALDH1B1 and ALDH2 were selected as suitable candidates. These were strongly and regularly expressed in tumour tissue and cell lines, including highly tumourigenic cell populations (ALDH+CD44+ cells), while other ALDHs, including ALDH1A1, showed differential or low expression. No genetic alteration of ALDH1B1 in CRC was suggested by the relationships between mRNA and protein levels/enzymatic activities, and cDNA sequences of CRC cell lines. Tissue microarray findings showed that ALDH1B1, but not ALDH2, could distinguish CRC from normal tissue. Furthermore, ratios of ALDH1B1 to ALDH1A1 or ALDH2 were found to be powerful CRC indicators.ConclusionsThese results suggest that ALDH1B1 is a novel human CRC biomarker.
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Project description:Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and 126 residents who did not drink in their daily lives (AUDIT score = 0), using high-density single nucleotide polymorphism (SNP) arrays. The rs671 G > A manifests the highest significance of the association with drinking behavior (Fisher's exact P = 8.75 × 10-9). It is a pleiotropic, non-synonymous variant in the aldehyde dehydrogenase 2 (ALDH2) gene. The minor allele "A", commonly known as ALDH2*2, is associated with non-drinkers. Intriguingly, identity-by-descent haplotypes encompassing genomic regions with a median length of 1.6 (0.6-2.0) million nucleotide bases were found in all study participants with either heterozygous or homozygous ALDH2*2 (n = 81 and 13, respectively). We also analyzed a public-domain dataset with genome-wide genotypes of 2000 participants in Guangzhou, a coastal city in Southern China. Among them, 175 participants have homozygous ALDH2*2 genotype, and again, long ALDH2*2-carrying haplotypes were found in all 175 participants without exceptions. The median length of the ALDH2*2-carrying haplotype is 1.7 (0.5-2.8) million nucleotide bases. The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014-9381) years ago. In conclusion, the rs671 G > A is the leading genomic variant associated with the long-term drinking behavior among residents of Keelung, Taiwan. The ALDH2*2 allele has been in Asian populations since prehistoric times.
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Project description:The dissociation of the aldehyde dehydrogenase X NADH complex was studied by displacement with NAD+. The association reaction of enzyme and NADH was also studied. These processes are biphasic, as shown by McGibbon, Buckley & Blackwell [(1977) Biochem. J. 165, 455-462], but the details of the dissociation reaction are significantly different from those given by those authors. Spectral and kinetic experiments provide evidence for the formation of abortive complexes of the type enzyme X NADH X aldehyde. Kinetic studies at different wavelengths with transcinnamaldehyde as substrate provide evidence for the formation of an enzyme X NADH X cinnamoyl complex. Hydrolysis of the thioester relieves a severe quenching effect on the fluorescence of enzyme-bound NADH.
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Project description:Thermoacidophilic archaea such as Thermoplasma acidophilum and Sulfolobus solfataricus are known to metabolize D-glucose via the nED (non-phosphorylated Entner-Doudoroff) pathway. In the present study, we identified and characterized a glyceraldehyde dehydrogenase involved in the downstream portion of the nED pathway. This glyceraldehyde dehydrogenase was purified from T. acidophilum cell extracts by sequential chromatography on DEAE-Sepharose, Q-Sepharose, Phenyl-Sepharose and Affi-Gel Blue columns. SDS/PAGE of the purified enzyme showed a molecular mass of approx. 53 kDa, whereas the molecular mass of the native protein was 215 kDa, indicating that glyceraldehyde dehydrogenase is a tetrameric protein. By MALDI-TOF-MS (matrix-assisted laser-desorption ionization-time-of-flight MS) peptide fingerprinting of the purified protein, it was found that the gene product of Ta0809 in the T. acidophilum genome database corresponds to the purified glyceraldehyde dehydrogenase. The native enzyme showed the highest activity towards glyceraldehyde, but no activity towards aliphatic or aromatic aldehydes, and no activity when NAD+ was substituted for NADP+. Analysis of the amino acid sequence and enzyme inhibition studies indicated that this glyceraldehyde dehydrogenase belongs to the ALDH (aldehyde dehydrogenase) superfamily. BLAST searches showed that homologues of the Ta0809 protein are not present in the Sulfolobus genome. Possible differences between T. acidophilum (Euryarchaeota) and S. solfataricus (Crenarchaeaota) in terms of the glycolytic pathway are thus expected.
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