Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer

Xanthis, Vasileios; Mantso, Theodora; Dimtsi, Anna; Pappa, Aglaia; Fadouloglou, Vasiliki E.

doi:10.3390/cancers15174419

Cited by 11 publications

(2 citation statements)

References 249 publications

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“…Tumor heterogeneity is also an important driver of drug resistance [32,80,210,211]. In contrast to non-CSCs, CSCs are characterized by specific features that allow them to escape drug toxicity [211,212]. These specific features include expression of different members of the ATP-binding cassette (ABC) transporters such as ABCB5, ABCG1, ABCG2, and ABCG5, all "efflux pumps", to extrude drugs from cells into the microenvironment [213,214].…”

Section: Mechanisms Of Melanoma Treatment Failure and Recurrencementioning

confidence: 99%

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

Al Hmada,

Brodell,

Kharouf

et al. 2024

Cancers

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Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

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Section: Mechanisms Of Melanoma Treatment Failure and Recurrencementioning

confidence: 99%

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

Al Hmada,

Brodell,

Kharouf

et al. 2024

Cancers

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“…ALDH3A1 serves a critical function in metabolizing a broad spectrum of aliphatic and aromatic aldehydes, safeguarding cells from oxidative damage, and maintaining cellular balance [23,24]. Dysregulation of this enzyme is implicated in an array of diseases, such as cancers and neurodegenerative disorders, highlighting its value as a target for therapeutic intervention across these conditions [25,26].…”

Section: Introductionmentioning

confidence: 99%

AI-driven drug discovery: identification and optimization of ALDH3A1 selective inhibitors with nanomolar activity

Jain,

Yasgar,

Dalal

et al. 2024

Preprint

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In the field of medicinal chemistry, the discovery of novel compounds with therapeutic potential is of utmost importance. However, the conventional approach to drug discovery, relying on high-throughput screening (HTS), encounters limitations such as reagent availability and labor costs. Although a hit-finding campaign starts with a virtual screen of millions of compounds, the hit-to-lead and lead optimization stages often require designing, synthesizing, and profiling thousands of analogs before selecting clinical candidates. Recent advances offer an innovative solution - the virtual generation of billions of synthetically feasible compounds with an impressive 80% success rate for synthesis. This breakthrough has the potential to significantly expand the chemical space available for purchase and experimental validation, bringing about a revolution in the field. Our study presents a comprehensive approach to compound discovery and optimization, harnessing quantitative high-throughput screening (qHTS), chemical databases, and reaction-based enumeration. To further enhance the synthesis process and gain deeper insights into compound formation, we utilize the Reaction Cookbook from Biosolveit, which comprises reaction SMARTs for around 300 chemical reactions. By employing this wide range of reactions, we aim to uncover the full spectrum of a chemotype's potential and customize its structure to optimize desired properties. As an illustration of this approach, our work on the ALDH3A1 project resulted in the synthesis of 50 compounds, with 21 of them exhibiting activity (negative curve class values; hit-rate ~42%). Among these active compounds, 6 displayed IC50 values lower than 30 µM and efficacy values less than -50%, with the most potent compound achieving an impressive potency of 447 nM. This study demonstrates the successful synergy between in-silico reaction-based analogs enumeration, molecular modeling and AI/ML-based techniques in identifying compounds with improved biological activity, offering promising prospects for the development of ALDH3A1-targeting agents as potential cancer therapeutics. Computational workflows developed in this study can be used for similar target-based drug discovery campaigns.

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Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy

Baldari,

Antonini,

Di Rocco

et al. 2024

Cancer Innovation

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BackgroundThe incidence of alcohol‐associated cancers is higher within Asian populations having an increased prevalence of an inactivating mutation in aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme required for the clearance of acetaldehyde, a cytotoxic metabolite of ethanol. The role of alcohol consumption in promoting lung cancer is controversial, and little attention has been paid to the association between alcohol drinking and pulmonary ALDH2 expression.MethodsWe performed a comprehensive bioinformatic analysis of multi‐omics data available in public databases to elucidate the role of ALDH2 in lung adenocarcinoma (LUAD).ResultsTranscriptional and proteomic data indicate a substantial pulmonary expression of ALDH2, which is functional for the metabolism of alcohol diffused from the bronchial circulation. ALDH2 expression is higher in healthy lung tissue than in LUAD and inhibits cell cycle, apoptosis, and epithelial–mesenchymal transition pathways. Moreover, low ALDH2 mRNA levels predict poor prognosis and low overall survival in LUAD patients. Interestingly, ALDH2 expression correlates with immune infiltration in LUAD.ConclusionsA better understanding of the role of ALDH2 in lung tumor progression and immune infiltration might support its potential use as a prognostic marker and therapeutic target for improving immunotherapeutic response.

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Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer

Cited by 11 publications

References 249 publications

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

AI-driven drug discovery: identification and optimization of ALDH3A1 selective inhibitors with nanomolar activity

Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy

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