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Disorders of Alcohol Metabolism in the Occurrence and Development of Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 13169

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Dr. Karolina Orywal

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Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15 A, 15-276 Białystok, Poland
Interests: alcohol dehydrogenase isoenzymes; aldehyde dehydrogenase; cancer diseases; protein; cytokine
Special Issues, Collections and Topics in MDPI journals

Dr. Beata Želazowska-Rutkowska

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Guest Editor

Department of Pediatric Laboratory Diagnostics, Medical University of Bialystok, Waszyngtona 17, 15-274 Białystok, Poland
Interests: chronic infection; children; endocrinology disease; cytokine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alcohol metabolism plays a crucial role in the occurrence and development of cancer. Ethanol, the primary ingredient in alcoholic beverages, undergoes metabolism in the body, resulting in various intermediates and byproducts that can have carcinogenic effects. The two main enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Disorders in the function or regulation of these enzymes can lead to the accumulation of toxic substances, such as acetaldehyde, contributing to cancer development.

Acetaldehyde is a highly reactive and toxic compound with mutagenic properties, which can induce DNA damage and interfere with DNA repair mechanisms. It can cause interstrand crosslinks in DNA, which are particularly difficult to repair and can lead to cancer if not correctly resolved. Moreover, variations in ADH and ALDH genes can affect enzyme activity. For instance, certain polymorphisms in the ALDH2 gene result in reduced enzyme activity, leading to higher levels of acetaldehyde after alcohol consumption. Populations with a high prevalence of this polymorphism, such as East Asians, are at an increased risk of alcohol-related cancers, particularly esophageal cancer. Alcohol metabolism also generates reactive oxygen species (ROS) as byproducts, contributing to oxidative stress. This oxidative stress can lead to further DNA damage, lipid peroxidation, and protein modification, all of which can contribute to carcinogenesis. Alcohol consumption can lead to epigenetic changes, such as DNA methylation and histone modification, which can alter gene expression patterns and contribute to cancer development. Acetaldehyde, through its interaction with DNA and histones, can disrupt normal epigenetic regulation. Furthermore, the human microbiome, particularly in the gut, also plays a role in alcohol metabolism. Some gut bacteria can metabolize ethanol to acetaldehyde, contributing to local and systemic acetaldehyde exposure. Dysbiosis, or an imbalance in the microbiome due to alcohol consumption, can exacerbate this effect and contribute to cancer risk.

Disorders in alcohol metabolism, particularly those leading to the accumulation of acetaldehyde and oxidative stress, play a significant role in the development of various cancers. Chronic alcohol consumption and the resulting acetaldehyde exposure are linked to several types of cancer like esophageal cancer, head and neck cancers, liver cancer or breast cancer. Understanding these metabolic pathways and their genetic and epigenetic regulation is crucial for identifying individuals at high risk and developing targeted prevention and treatment strategies for alcohol-related cancers.

In this Special Issue, we welcome original research and literature reviews discussing various aspects of alcohol metabolism disorders in relation to tumorigenesis to summarize and enlarge our understanding of the meaning of alcohol consumption in the occurrence and development of cancer diseases.

Dr. Karolina Orywal
Dr. Beata Želazowska-Rutkowska
Guest Editors

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Keywords

aldehyde dehydrogenase
molecular regulation
molecular tumor pathology
gene polymorphism
gene expression
polymorphism
ALDH isoenzymes
ALDH inhibitors
therapeutic targets
prognosis
cancer stem cell
stem cell marker
biomarker
retinoic acid
oxidative stress
toxic aldehydes
tumor microenvironment
angiogenesis
metastasis

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Research

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26 pages, 5644 KiB

Open AccessArticle

Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma

by Rafael Jiménez, Andrada Constantinescu, Muhube Yazir, Paula Alfonso-Triguero, Raquel Pequerul, Xavier Parés, Mileidys Pérez-Alea, Ana Paula Candiota, Jaume Farrés and Julia Lorenzo

Int. J. Mol. Sci. 2024, 25(21), 11512; https://doi.org/10.3390/ijms252111512 - 26 Oct 2024

Cited by 1 | Viewed by 1515

Abstract

Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40–50%. Full article

(This article belongs to the Special Issue Disorders of Alcohol Metabolism in the Occurrence and Development of Cancer)

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17 pages, 3223 KiB

Open AccessArticle

Exploring the Role and Pathophysiological Significance of Aldehyde Dehydrogenase 1B1 (ALDH1B1) in Human Lung Adenocarcinoma

by Ilias Tsochantaridis, Dimitris Brisimis, Margaritis Tsifintaris, Anastasia Anastasiadou, Efthymios Lazos, Antreas Ermogenous, Sylia Christou, Nefeli Antonopoulou, Mihalis I. Panayiotidis, Michail I. Koukourakis, Alexandra Giatromanolaki and Aglaia Pappa

Int. J. Mol. Sci. 2024, 25(19), 10301; https://doi.org/10.3390/ijms251910301 - 25 Sep 2024

Cited by 1 | Viewed by 2855

Abstract

Aldehyde dehydrogenases (ALDHs) constitute a diverse superfamily of NAD(P)⁺-dependent enzymes pivotal in oxidizing endogenous and exogenous aldehydes to carboxylic acids. Beyond metabolic roles, ALDHs participate in essential biological processes, including differentiation, embryogenesis and the DNA damage response, while also serving as markers for cancer stem cells (CSCs). Aldehyde dehydrogenase 1B1 (ALDH1B1) is a mitochondrial enzyme involved in the detoxification of lipid peroxidation by-products and metabolism of various aldehyde substrates. This study examines the potential role of ALDH1B1 in human lung adenocarcinoma and its association with the CSC phenotype. To this end, we utilized the lung adenocarcinoma cell line A549, engineered to stably express the human ALDH1B1 protein tagged with green fluorescent protein (GFP). Overexpression of ALDH1B1 led to notable changes in cell morphology, proliferation rate and clonogenic efficiency. Furthermore, ALDH1B1-overexpressing A549 cells exhibited enhanced resistance to the chemotherapeutic agents etoposide and cisplatin. Additionally, ALDH1B1 overexpression correlated with increased migratory potential and epithelial–mesenchymal transition (EMT), mediated by the upregulation of transcription factors such as SNAI2, ZEB2 and TWIST1, alongside the downregulation of E-cadherin. Moreover, Spearman’s rank correlation coefficient analysis using data from 507 publicly available lung adenocarcinoma clinical samples revealed a significant correlation between ALDH1B1 and various molecules implicated in CSC-related signaling pathways, including Wnt, Notch, hypoxia, Hedgehog, retinoic acid, Hippo, NF-κΒ, TGF-β, PI3K/PTEN-AKT and glycolysis/gluconeogenesis. These findings provide insights into the role of ALDH1B1 in lung tumor progression and its relation to the lung CSC phenotype, thereby offering potential therapeutic targets in the clinical management of lung adenocarcinoma. Full article

(This article belongs to the Special Issue Disorders of Alcohol Metabolism in the Occurrence and Development of Cancer)

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18 pages, 4838 KiB

Open AccessArticle

Identifying the Molecular Drivers of Pathogenic Aldehyde Dehydrogenase Missense Mutations in Cancer and Non-Cancer Diseases

by Dana Jessen-Howard, Qisheng Pan and David B. Ascher

Int. J. Mol. Sci. 2023, 24(12), 10157; https://doi.org/10.3390/ijms241210157 - 15 Jun 2023

Cited by 2 | Viewed by 2606

Abstract

Human aldehyde dehydrogenases (ALDHs) comprising 19 isoenzymes play a vital role on both endogenous and exogenous aldehyde metabolism. This NAD(P)-dependent catalytic process relies on the intact structural and functional activity of the cofactor binding, substrate interaction, and the oligomerization of ALDHs. Disruptions on the activity of ALDHs, however, could result in the accumulation of cytotoxic aldehydes, which have been linked with a wide range of diseases, including both cancers as well as neurological and developmental disorders. In our previous works, we have successfully characterised the structure–function relationships of the missense variants of other proteins. We, therefore, applied a similar analysis pipeline to identify potential molecular drivers of pathogenic ALDH missense mutations. Variants data were first carefully curated and labelled as cancer-risk, non-cancer diseases, and benign. We then leveraged various computational biophysical methods to describe the changes caused by missense mutations, informing a bias of detrimental mutations with destabilising effects. Cooperating with these insights, several machine learning approaches were further utilised to investigate the combination of features, revealing the necessity of the conservation of ALDHs. Our work aims to provide important biological perspectives on pathogenic consequences of missense mutations of ALDHs, which could be invaluable resources in the development of cancer treatment. Full article

(This article belongs to the Special Issue Disorders of Alcohol Metabolism in the Occurrence and Development of Cancer)

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Review

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28 pages, 1236 KiB

Open AccessReview

The Significance of Aldehyde Dehydrogenase 1 in Cancers

by Anh L. Nguyen, Caroline O. B. Facey and Bruce M. Boman

Int. J. Mol. Sci. 2025, 26(1), 251; https://doi.org/10.3390/ijms26010251 - 30 Dec 2024

Cited by 1 | Viewed by 1729

Abstract

The goal of this paper is to discuss the role of ALDH isozymes in different cancers, review advances in ALDH1-targeting cancer therapies, and explore a mechanism that explains how ALDH expression becomes elevated during cancer development. ALDH is often overexpressed in cancer, and each isoform has a unique expression pattern and a distinct role in different cancers. The abnormal expression of ALDHs in different cancer types (breast, colorectal, lung, gastric, cervical, melanoma, prostate, and renal) is presented and correlated with patient prognosis. ALDH plays a significant role in various cellular functions, such as metabolism, oxidative stress response, detoxification, and cellular differentiation. Among the ALDH families, ALDH1 has gained considerable attention as a cancer stem cell (CSC) marker due to its significant role in the maintenance of stemness and the differentiation of stem cells (SCs), along with its involvement in tumorigenesis. A description of the cellular mechanisms and physiology of ALDH1 that underlies cancer development is provided. Moreover, current advances in ALDH1-targeting cancer therapies are discussed. Full article

(This article belongs to the Special Issue Disorders of Alcohol Metabolism in the Occurrence and Development of Cancer)

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19 pages, 864 KiB

Open AccessReview

The Molecular Context of Oxidant Stress Response in Cancer Establishes ALDH1A1 as a Critical Target: What This Means for Acute Myeloid Leukemia

by Garrett M. Dancik, Lokman Varisli and Spiros A. Vlahopoulos

Int. J. Mol. Sci. 2023, 24(11), 9372; https://doi.org/10.3390/ijms24119372 - 27 May 2023

Cited by 13 | Viewed by 3310

Abstract

The protein family of aldehyde dehydrogenases (ALDH) encompasses nineteen members. The ALDH1 subfamily consists of enzymes with similar activity, having the capacity to neutralize lipid peroxidation products and to generate retinoic acid; however, only ALDH1A1 emerges as a significant risk factor in acute myeloid leukemia. Not only is the gene ALDH1A1 on average significantly overexpressed in the poor prognosis group at the RNA level, but its protein product, ALDH1A1 protects acute myeloid leukemia cells from lipid peroxidation byproducts. This capacity to protect cells can be ascribed to the stability of the enzyme under conditions of oxidant stress. The capacity to protect cells is evident both in vitro, as well as in mouse xenografts of those cells, shielding cells effectively from a number of potent antineoplastic agents. However, the role of ALDH1A1 in acute myeloid leukemia has been unclear in the past due to evidence that normal cells often have higher aldehyde dehydrogenase activity than leukemic cells. This being true, ALDH1A1 RNA expression is significantly associated with poor prognosis. It is hence imperative that ALDH1A1 is methodically targeted, particularly for the acute myeloid leukemia patients of the poor prognosis risk group that overexpress ALDH1A1 RNA. Full article

(This article belongs to the Special Issue Disorders of Alcohol Metabolism in the Occurrence and Development of Cancer)

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