No / Aldehyde dehydrogenases (ALDHs) belong to a superfamily of 19 isozymes that are known to participate in many physiologically important biosynthetic processes including detoxification of specific endogenous and exogenous aldehyde substrates. The high expression levels of an emerging number of ALDHs in various cancer tissues suggest that these enzymes have pivotal roles in cancer cell survival and progression. Mapping out the heterogeneity of tumours and their cancer stem cell (CSC) component will be key to successful design of strategies involving therapeutics that are targeted against specific ALDH isozymes. This review summarises recent progress in ALDH-focused cancer research and discovery of small-molecule-based inhibitors.

Yes / Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.

The aldehyde dehydrogenase (ALDH) superfamily is gaining momentum in regard to stem cell and cancer research. However, their regulation and expression in the cancer microenvironment is poorly understood. The aim of this work was to understand the role of selected ALDH isoforms (1A1, 1A2, 1A3, 1B1, 2, 3A1 and 7A1) in colorectal cancer (CRC) and explore the impact of hypoxia on their expression. CRC cell lines (HT29, DLD-1, SW480 and HCT116) were grown under normoxic or hypoxic conditions (0.1% O2) and HT29 and DLD-1 in spinner flasks to generate multicellular spheroids (MCS). Hypoxia was demonstrated to have an impact on the ALDH expression, which appeared cell-specific. Notably, ALDH7A1 was induced upon exposure to hypoxia in both HT29 and DLD-1 cells, shown to be expressed in the hypoxic region of the MCS variants and in 5/5 CRC xenografts (HT29, DLD-1, HCT116, SW620, and COLO205). ALDH7A1 siRNA knockdown studies in DLD-1 cells resulted in significant reduction of viable cells and significant increase in ROS levels, suggesting ALDH7A1 to possess antioxidant properties. These findings were further supported using isogenic H1299/RFP and H1299/ALDH7A1 lung cancer cell lines. ALDH7A1, however, was found not to be involved in inhibiting the pharmacological effect or causing resistance to different cytotoxic and molecularly targeted anticancer drugs. To unravel the functional role of ALDH7A1, 9 compounds obtained from a virtual screening of 24,000 compounds from the Maybridge collection of compounds were used to probe ALDH7A1 functional activity. One compound, HAN00316, was found to inhibit the antioxidant properties of ALDH7A1 and thus could be a good starting point for further chemical tool development. Although this study underpins a potential important role of ALDH7A1 in hypoxic CRC, further work is required to fully validate its potential as a biomarker and/or pharmacological target. / Jordan University of Science and Technology

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The cancer stem cell (CSC) concept is still very controversial; therefore identification and isolation of this specific population remain challenging. A variety of putative markers have been described and measurement of high aldehyde dehydrogenase (ALDH) activity has been defined as a characteristic of stem cells (SCs). In this study, a library of novel small molecules (1,4-disubstituted acetalanthraquinones, AAQs), containing an acetal group as protected aldehyde functionality, was designed with the aim of probing affinity for ALDH metabolism and demonstrating their potential as molecular fluorescent probes to identify CSCs. The AAQs were shown to be subjective to acidic hydrolysis using 2M HCl at 37ºC; however compounds containing secondary or tertiary amine functionalities in their sidechain were only partly hydrolysed at 70 ºC. Metabolism studies were conducted using cytosolic fractions from rat liver enriched in ALDHs, yeast ALDH and human recombinant ALDH1A1. Some evidence was demonstrated which linked ALDH metabolism with aldehyde functionalities of hydrolysed AAQs (HAAQs). The AAQs were shown to emit far-red fluorescence (600-750 nm). A close relationship between structure modifications and alteration of cellular localisation, with gained specificity for selected sub-cellular compartments were achieved when assessed in A549 and U-2 OS cell lines. Thermal DNA denaturation and chemosensitivity assays were used to obtain information about DNA binding properties and cytotoxicity of AAQs and HAAQ congeners. All compounds were shown to be weak-to-moderately binding to DNA, and symmetrical 1,4-disubstituted compounds were shown to be non-toxic (IC50 = 100 :M) with nonsymmetrical analogues generating IC50 values in the 1-100 :M range. No fundamental variation in the biological activity was observed when comparing AAQs with HAAQs in the A549 (+ALDH) and MCF7 (-ALDH) cell lines. A pilot investigation revealed that aberrant gene methylation was cell-type dependent for three ALDH isoforms (1A1, 2, 3A1). Decitabine treatment led to enhanced protein expression for ALDH1A1 (A549), ALDH2 (MCF7) and ALDH3A1 (A549). In contrast, the protein level was reduced for ALDH1A1 in HT29 cells after decitabine treatment. ALDH1A1, ALDH2 and ALDH3A1 were highly expressed in prostate cell lines, with expression linked to promoter methylation. In contrast, low levels of DNA methylation were found in primary prostate cancer cells and benign prostatic hyperplasia. Interestingly, ALDH1A1, considered a SC marker, was found to be expressed at low levels in CD133⁺/ α₂β₁ hi stem cell fraction and upregulated in CD133⁻/ α₂β₁ lo differentiated prostate cancer cells. In summary, the results in this thesis demonstrate the complexity and tumour type specificity of ALDH expression. This creates challenges for the development of selective probes for CSC isolation, such as the AAQs discussed in this thesis. Although inconclusive results were obtained in regard to AAQs and their potential in targeting ALDHs, selected AAQs were shown to reveal interesting biological features highlighting them as potential non-invasive cytometric probes for tracking molecular interactions in live cells.

A alta atividade da enzima Aldeído-desidrogenase (ALDH) tem sido relatada como um marcador das células troncos tumorais (CTT) no câncer de mama. Sabe-se que essas células estão envolvidas na resistência ao tratamento radio e quimioterápico e podem ser responsáveis pela recorrência e disseminação metastática. A associação entre a quantidade de CTTs e a resposta a quimioterapia neoadjuvante (QNA) ainda não está estabelecida. Foi analisado retrospectivamente a expressão de ALDH1A1 por imunohistoquímica (IHQ) em amostras previamente analisadas por citometria de fluxo para ALDH1A1 no tumor primário de 61 pacientes com carcinoma ductal invasivo diagnosticado entre 2010 e 2012. A maioria das pacientes estava entre 51-70 anos (59%), na menopausa (65,6%) e com estádio clínico III (47,5%). A expressão positiva de receptores de estrógeno, progesterona e de HER2 foi de 67,2%, 52,5% e 45,9% respectivamente. A imunohistoquímica para ALDH1A1 foi realizada com lâminas da TMA e considerado positivos os casos com marcação citoplástica evidente em grupamentos de 5 ou mais células. Foi analisada a associação entre esses dados e o resultado da citometria de fluxo para ALDH1 e também a associação com os fatores prognósticos conhecidos. Não foi encontrada associação (p = 0,67) entre a porcentagem de células ALDH1+ com o resultado da imunohistoquímica positiva para ALDH1A1 (4,45% (1,7 - 10,1)) e negativa (3,2% (1,2 - 13,6)). Os dados não demonstraram associação da IHQ para ALDH1A1 ou da quantia de células ALDH1+ no tumor primário com a resposta patológica completa após quimioterapia neoadjuvante, sugerindo que essa população pode não ser um fator preditor isolado da resposta a QNA. Também não foi observado relação da IHQ para ALDH1A1 com os fatores prognósticos conhecidos. A sobrevida também não foi influenciada pela expressão de ALDH1A1 pela IHQ tanto na sobrevida global (p = 0,54; HR = 1,33 (0,52 - 3,39)) quanto na livre de doença (p = 0,35; HR = 1,67 (0,57 - 4,90)). Quanto a porcentagem de células ALDH1+ no tumor primário, também não houve impacto sobre a sobrevida global (p = 0,40; HR = 0,98 (0,92 - 1,03)), nem na sobrevida livre de doença (p = 0,55; HR = 0,98 (0,92 - 1,05)). A presença de células ALDH1A1 positivas na imunohistoquímica não se relaciona com a atividade da enzima analisada por citometria de fluxo e não apresenta associação com fatores prognósticos / The expressions of aldehyde-dehydrogenase (ALDH) has been reported as potential breast cancer stem-like cells (BCSLCs) markers. Those cells are known to be involved with treatment resistance and may be responsible for relapses and metastatic dissemination. The association between the quantity of BCSLCs and the response to neoadjuvant chemotherapy (NACT) remains unclear. We retrospectively analyzed the expression of ALDH1A1 by immunohistochemistry (IHQ) in 61 patients with invasive ductal carcinomas of the breast from 2010 to 2012 previously analyzed by flow cytometry (FCT). Most patients were aged between 51-70 years (59%), clinical stage III (47,5%) and menopausal (65,6%). The ER, PgR and HER2 positive expression rates were 67,2%, 52,5% and 45,9%, respectively. The aldehyde-dehydrogenase immunohistochemistry ware evaluated by TMA and considered to be positive cases with evident cytoplasmic staining in clusters of 5 or more cells. These data were correlated with the flow cytometry results and clinical and pathological features. No association between ALDH1+ cell population by FCT with ALDH1A1 positive (4,45% (1,7 - 10,1)) and negative (3,2% (1,2 - 13,6)) cases by IHQ were observed (p= 0,67). No relationship between ALDH1A1+ by IHQ nor ALDH1+ by FCT were found with the complete pathological response to therapy, suggesting that it might not be an isolated predictor of response to NACT. No relationship between IHQ was found with the clinicalpathological features. The overall survival was the same between the two groups by IHQ (p = 0,54; HR = 1,33 (0,52 - 3,39)) and also the disease free survival (p = 0,35; HR = 1,67 (0,57 - 4,90)). The FCT results did not correlate with the overall survival (p = 0,40; HR = 0,98 (0,92 - 1,03)), nor with the disease free survival (p = 0,55; HR = 0,98 (0,92 - 1,05)). The expression of ALDH1A1+ by immunohistochemistry have no association with the enzymatic function analyzed by flow cytometry and do not represent a prognostic factor

Deux familles d'aldéhyde déshydrogénases (ALDH) phylogénétiquement et structuralement distinctes catalysent l'oxydation des aldéhydes : les ALDH phosphorylantes et les ALDH non phosphorylantes. Ces enzymes jouent un rôle essentiel au niveau cellulaire en intervenant au niveau du métabolisme et dans des processus de détoxication. En 2003, la résolution de la structure tridimensionnelle de l'enzyme bifonctionnelle 4-hydroxy-2-cétovalérate aldolase/acétaldéhyde déshydrogénase (DmpFG) de Pseudomonas sp. CF600 a permis l'identification d'une nouvelle famille d'ALDH : la sous-unité DmpF étant structuralement apparentée aux ALDH phosphorylantes alors qu'elle présente une activité de type non phosphorylante CoA-dépendante. Par la caractérisation enzymatique et structurale des orthologues MhpEF issus d'Escherichia coli et de Thermomonospora curvata, nos travaux montrent que les paramètres cinétiques de MhpF ne dépendent pas de son état oligomérique, ce qui est cas unique pour les ALDH. De plus, la résolution des structures cristallographiques de l'enzyme complexée avec du NAD+ ou du CoA, couplée à la structure en solution de la forme apoenzyme obtenue par SAXS montrent que le Rossmann fold s'accomode de la présence des cofacteurs par un vaste changement conformationnel. Enfin, l'étude du mécanisme catalytique et la résolution de la structure thioacylenzyme permettent d'identifierla MhpF comme étant un hybride des deux familles d'ALDH caractérisées jusqu'à présent / Two phylogenetically and structurally unrelated families of NAD(P)-dependent aldehyde dehydrogenases (ALDH) catalyze the oxidation of aldehydes into activated or non-activated acids. These enzymes are known to be involved in many biological functions such as cellular differentiation, central metabolism, or detoxification pathways. The crystal structure of the bifunctional enzyme, 4-hydroxy-2-ketovalerate aldolase (DmpG)/acetaldehyde dehydrogenase (DpmF) from Pseudomonas sp. CF600, leads to the identification of a new ALDH family. The DmpF subunit exhibits a non-phosphorylating CoA-dependent aldehyde dehydrogenase activity while its structure belongs to the phosphorylating ALDH superfamily. The kinetics of the MhpEF orthologs from Escherichia coli and Thermomonospora curvata show that the kinetic parameters of MhpF do not depend of its oligomeric state, which is unique for an ALDH. In addition, the crystal structures of the enzyme with NAD+ or CoA, as well as the solution structure of the apoenzyme using SAXS, reveal the dynamics of the overall Rossmann fold between apo or cofactors-bound conformers, which is necessary to carry on the catalytic cycle. Finally, the catalytic mechanism and the structure of the thioacylenzyme intermediates indicate that MhpF is a hybrid between both ALDH families characterized to date

Alcoholic steatosis (AS) is the initial pathology associated with early stage alcoholic liver disease and is characterized by the accumulation of fat in the liver. AS is considered clinically benign as it is reversible, as compared with alcoholic steatohepatitis (ASH) which is the next stage of alcoholic liver disease (ALD), and mostly irreversible. Proteomics were used to investigate the molecular basis of AS to determine biomarkers representative of AS. Liver tissue proteins at different stages of steatosis from a rodent model of AS were separated by two dimensional electrophoresis (2DE), followed by MALDI mass spectrometry (MS) identification of significantly expressed proteins. Expression levels of several proteins related to alcohol induced oxidative stress, such as peroxiredoxin 6 (PRDX6) and aldehyde dehydrogenase 2 (ALDH2) were reduced by 2 to 3-fold in ethanol fed rats, and suggested an increase in oxidative stress. Several proteins involved in fatty acid and amino acid metabolism were found at increased expression levels, suggesting higher energy demand upon chronic exposure to ethanol. In order to delineate between the effects of fat accumulation and oxidative stress, an in vitro hepatocyte cell culture model of steatosis was developed. HepG2 cells loaded with oleic acid surprisingly demonstrated lower cytotoxicity upon oxidative challenge (based on lactate dehydrogenase activity) and inflammation (based on TNF-? induced activation of the pro-inflammatory transcription factor NF-?B). We also examined the effect of oleic acid loading in HepG2 cells on protein carbonylation, which is an important irreversible protein modification during oxidative stress that leads to protein dysfunction and disease. Fat-loaded hepatocytes exposed to oxidative stress with tert-butyl hydroperoxide (TBHP) contained 17% less carbonylated proteins than the non-fat loaded control. Mass spectrometric analysis of carbonylated proteins indicated that known classical markers of protein carbonylation (e.g., cytoskeletal proteins, chaperones) are not carbonylated in oleic acid loaded HepG2 cells, and suggests that the protective effect of fat loading is through interference with protein carbonylation. While counterintuitive to the general concept that AS increases oxidative stress, our fat loading results suggests that low levels of fat may activate antioxidant pathways and ameliorate the effect of subsequent oxidative or inflammatory challenge.

Alcoholic steatosis (AS) is the initial pathology associated with early stage alcoholic liver disease and is characterized by the accumulation of fat in the liver. AS is considered clinically benign as it is reversible, as compared with alcoholic steatohepatitis (ASH) which is the next stage of alcoholic liver disease (ALD), and mostly irreversible. Proteomics were used to investigate the molecular basis of AS to determine biomarkers representative of AS. Liver tissue proteins at different stages of steatosis from a rodent model of AS were separated by two dimensional electrophoresis (2DE), followed by MALDI mass spectrometry (MS) identification of significantly expressed proteins. Expression levels of several proteins related to alcohol induced oxidative stress, such as peroxiredoxin 6 (PRDX6) and aldehyde dehydrogenase 2 (ALDH2) were reduced by 2 to 3-fold in ethanol fed rats, and suggested an increase in oxidative stress. Several proteins involved in fatty acid and amino acid metabolism were found at increased expression levels, suggesting higher energy demand upon chronic exposure to ethanol. In order to delineate between the effects of fat accumulation and oxidative stress, an in vitro hepatocyte cell culture model of steatosis was developed. HepG2 cells loaded with oleic acid surprisingly demonstrated lower cytotoxicity upon oxidative challenge (based on lactate dehydrogenase activity) and inflammation (based on TNF-? induced activation of the pro-inflammatory transcription factor NF-?B). We also examined the effect of oleic acid loading in HepG2 cells on protein carbonylation, which is an important irreversible protein modification during oxidative stress that leads to protein dysfunction and disease. Fat-loaded hepatocytes exposed to oxidative stress with tert-butyl hydroperoxide (TBHP) contained 17% less carbonylated proteins than the non-fat loaded control. Mass spectrometric analysis of carbonylated proteins indicated that known classical markers of protein carbonylation (e.g., cytoskeletal proteins, chaperones) are not carbonylated in oleic acid loaded HepG2 cells, and suggests that the protective effect of fat loading is through interference with protein carbonylation. While counterintuitive to the general concept that AS increases oxidative stress, our fat loading results suggests that low levels of fat may activate antioxidant pathways and ameliorate the effect of subsequent oxidative or inflammatory challenge.