Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets

Clark, David W.; Palle, Komaraiah

doi:10.21037/atm.2016.11.82

Cited by 180 publications

(159 citation statements)

References 73 publications

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“…ALDHs such as the 1A3 isoform could be a key player in such therapeutic intervention. However, as we [45] and others [46,87,222] have discussed previously, the expression of ALDHs in normal tissue expression remain a stumbling block towards a credible clinical therapy. However, advances in drug delivery technologies could in the future enable administration of an ALDH inhibitor, which is potently selective for a specific isoform.…”

Section: Aldh Hypoxia and Tmementioning

confidence: 82%

Expression and regulation of aldehyde dehydrogenases in prostate cancer

Ibrahim¹,

Sadiq²,

Frame³

et al. 2018

JCMT

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The functional role of aldehyde dehydrogenases (ALDHs) in prostate cancer remains an area of some controversy. Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties, while evidence is also emerging about the involvement of specific isoforms in migration, invasiveness and metastasis. Identification of specific ALDH isoforms, which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer. The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention. ABSTRACTArticle history:

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Section: Aldh Hypoxia and Tmementioning

confidence: 82%

Expression and regulation of aldehyde dehydrogenases in prostate cancer

Ibrahim¹,

Sadiq²,

Frame³

et al. 2018

JCMT

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“…Some recent studies have shown dual expression of ALDH1 with CD44 (ALDH1 + CD44 + ) or CD133 (ALDH1 + CD133 + ) in primary ovarian tumour samples and linked that with reduced disease-free and overall survival in OC patients [215][216][217][218]. ALDH1 promotes tumour cell survival by reducing the in vivo cytotoxic damage induced by the oxidized aldehydes [218,219]. The enzyme also detoxifies residual cytotoxic materials left after chemotherapy treatment conferring resistance to ALDH1 + cells [218,219].…”

Section: Csc-based Therapymentioning

confidence: 99%

“…ALDH1 promotes tumour cell survival by reducing the in vivo cytotoxic damage induced by the oxidized aldehydes [218,219]. The enzyme also detoxifies residual cytotoxic materials left after chemotherapy treatment conferring resistance to ALDH1 + cells [218,219]. Few recent studies have explored ALDH as an attractive antigenic target for inducing ALDH specific immune responses [220].…”

Section: Csc-based Therapymentioning

confidence: 99%

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...

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“…RA signaling is critical for the transcriptional control of many genes, and ALDH1A enzymes have received attention as potential drug targets. 2–7 …”

mentioning

confidence: 99%

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors

et al. 2017

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Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in (R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles.

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Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets

Cited by 180 publications

References 73 publications

Expression and regulation of aldehyde dehydrogenases in prostate cancer

Expression and regulation of aldehyde dehydrogenases in prostate cancer

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors

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