FIG 8 - uploaded by Risto O Juvonen
Content may be subject to copyright.
Antioxidant isoflavones. Inhibition of ALDH2 by daidzin and CVT-10216 is dependent on a conserved isoflavone moiety (box) and a 4-substituent identified as the essential pharmacophore.
Source publication
Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and developm...
Contexts in source publication
Context 1
... daidzein, and puerarin are phytochemicals derived from the Chinese edible vine Pueraria lobata. They have been used for cancer prevention and antidip- sotropic treatments in ancient Chinese medicine ( Keung and Vallee, 1993;McGregor, 2007). Daidzin (7-O-gluco- syl-4-hydroxyisoflavone) (Fig. 8), and its structural an- alogs are among the very few highly potent inhibitors of the ALDH2 isozyme (IC 50 , 80 nM) ( Lowe et al., 2008). Structural requirements of these molecules for ALDH2 inhibition include a polar 4-substituent with hydrogen binding capacity, such as NH 2 and OH, and an iso- flavone group that blocks the substrate ...
Context 2
... new analogs of daidzin have been devel- oped as highly selective, reversible inhibitors of ALDH2. For example, CVT-10216 ( Fig. 8) shows an IC 50 of 29 nM for ALDH2 and 1300 nM for ALDH1 ( Arolfo et al., 2009). An additional advantage of these inhibitors is their min- imal effect on monoamine oxidase ( Yao et al., 2010). CVT-10216 has also seen application in cocaine addic- tion, where inhibition of ALDH2 causes aberrant dopa- mine metabolism, leading to the ...
Citations
... Therefore, patients with high ALDH1A1 expression level had a poorer prognosis and therapeutic response than those with low levels (Schäfer et al., 2012). Diethyldithiocarbamate inhibits ALDH1A1 via its thiol affinity, forming a disulfide bond in the active site (Koppaka et al., 2012;Abu-Serie, 2018). In DE-FeO NPs-treated GSCs and GSC-RR, the inhibition of ALDH1A1 activity was associated with lowering ALDH1A1 gene expression. ...
The development of effective therapy for eradicating glioblastoma stem cells remains a major challenge due to their aggressive growth, chemoresistance and radioresistance which are mainly conferred by aldehyde dehydrogenase (ALDH)1A1. The latter is the main stemness mediator via enhancing signaling pathways of Wnt/β-catenin, phosphatidylinositol 3-kinase/AKT, and hypoxia. Furthermore, ALDH1A1 mediates therapeutic resistance by inactivating drugs, stimulating the expression of drug efflux transporters, and detoxifying reactive radical species, thereby apoptosis arresting. Recent reports disclosed the potent and broad-spectrum anticancer activities of the unique nanocomplexes of diethyldithiocarbamate (DE, ALDH1A1 inhibitor) with ferrous oxide nanoparticles (FeO NPs) mainly conferred by inducing lipid peroxidation-dependent non-apoptotic pathways (iron accumulation-triggered ferroptosis), was reported. Accordingly, the anti-stemness activity of nanocomplexes (DE-FeO NPs) was investigated against human and mouse glioma stem cells (GSCs) and radioresistant GSCs (GSCs-RR). DE-FeO NPs exhibited the strongest growth inhibition effect on the treated human GSCs (MGG18 and JX39P), mouse GSCs (GS and PDGF-GSC) and their radioresistant cells (IC50 ≤ 70 and 161 μg/mL, respectively). DE-FeO NPs also revealed a higher inhibitory impact than standard chemotherapy (temozolomide, TMZ) on self-renewal, cancer repopulation, chemoresistance, and radioresistance potentials. Besides, DE-FeO NPs surpassed TMZ regarding the effect on relative expression of all studied stemness genes, as well as relative p-AKT/AKT ratio in the treated MGG18, GS and their radioresistant (MGG18-RR and GS-RR). This potent anti-stemness influence is primarily attributed to ALDH1A1 inhibition and ferroptosis induction, as confirmed by significant elevation of cellular reactive oxygen species and lipid peroxidation with significant depletion of glutathione and glutathione peroxidase 4. DE-FeO NPs recorded the optimal LogP value for crossing the blood brain barrier. This in vitro novel study declared the potency of DE-FeO NPs for collapsing GSCs and GSCs-RR with improving their sensitivity to chemotherapy and radiotherapy, indicating that DE-FeO NPs may be a promising remedy for GBM. Glioma animal models will be needed for in-depth studies on its safe effectiveness.
... These included recognized metabolic disease-associated proteins such as PCSK9, LDLR, FURIN, FABP1 and FABP4. Other associated proteins metabolise hydroxysteroids, retinol and lipids, including ALDH1A1 and ADH4, which may regulate the metabolic response to a high fat diet 32,33 . Other proteins are potential contributors to diabetes and metabolic disease, GGT1 34 , or their complications, SORD 35 . ...
Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic and proteomic study, we expand the number of genetic loci from 19 to 29, and identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to a larger functional ovarian reserve. Hormonal regulation in the aetiology of this condition, through metabolic and reproductive features, was emphasised. The proteomic analysis highlighted perturbations of metabolically-related biology that are typical in women with PCOS. A PCOS polygenic risk score was associated with adverse cardio-metabolic outcomes, with differing contributions of testosterone and BMI in women and men. Finally, while oligo- and anovulatory infertility are characteristic features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.
... In recent years, research has revealed that the activity of ALDH and its family members, such as ALDH1A1, in certain tumor stem cells (CSCs) is generally higher than in normal tissues (Yang et al., 2018). Transcriptional activation of ALDH1 expression has been associated with drug resistance in tumors (Koppaka et al., 2012). CSCs are considered a subset of cancer cells. ...
Disulfiram (DSF) is a second-line drug for the clinical treatment of alcoholism and has long been proven to be safe for use in clinical practice. In recent years, researchers have discovered the cancer-killing activity of DSF, which is highly dependent on the presence of metal ions, particularly copper ions. Additionally, free DSF is highly unstable and easily degraded within few minutes in blood circulation. Therefore, an ideal DSF formulation should facilitate the co-delivery of metal ions and safeguard the DSF throughout its biological journey before reaching the targeted site. Extensive research have proved that nanotechnology based formulations can effectively realize this goal by strategic encapsulation therapeutic agents within nanoparticle. To be more specific, this is accomplished through precise delivery, coordinated release of metal ions at the tumor site, thereby amplifying its cytotoxic potential. Beyond traditional co-loading techniques, innovative approaches such as DSF-metal complex and metal nanomaterials, have also demonstrated promising results at the animal model stage. This review aims to elucidate the anticancer mechanism associated with DSF and its reliance on metal ions, as well as to provide a comprehensive overview of recent advances in the arena of nanomedicine based co-delivery strategies for DSF and metal ion in the context of cancer therapy.
... Disulfiram (DIS), developed in the 19 th century, inhibits aldehyde dehydrogenase and is an effective therapeutic agent for the treatment and management of alcoholism. 112 A recent study has revealed that DIS is an effective inhibitor of GSDMD pore-forming protein. 113 Previous studies suggest that DIS mitigates robust inflammation and the formation of fibrosis by inhibiting the activation of canonical pyroptosis in a variety of diseases. ...
Pyroptosis defines a form of pro-inflammatory-dependent programmed cell death triggered by gasdermin proteins, which creates cytoplasmic pores and promotes the activation and accumulation of immune cells by releasing several pro-inflammatory mediators and immunogenic substances upon cell rupture. Pyroptosis comprises canonical (mediated by Caspase-1) and non-canonical (mediated by Caspase-4/5/11) molecular signaling pathways. Numerous studies have explored the contributory roles of inflammasome and pyroptosis in the progression of multiple pathological conditions such as tumors, nerve injury, inflammatory diseases and metabolic disorders. Accumulating evidence indicates that the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome results in the activation of pyroptosis and inflammation. Current evidence suggests that pyroptosis-dependent cell death plays a progressive role in the development of diabetic complications including diabetic wound healing (DWH) and diabetic foot ulcers (DFUs). This review presents a brief overview of the molecular mechanisms underlying pyroptosis and addresses the current research on pyroptosis-dependent signaling pathways in the context of DWH. In this review, we also present some prospective therapeutic compounds/agents that can target pyroptotic signaling pathways, which may serve as new strategies for the effective treatment and management of diabetic wounds.
... Cysteine residues can be targeted with high selectivity due to the unique reactivity (nucleophilicity and polarizability) of the thiolate functional group. This is evidenced by numerous drugs that form covalent bonds to cysteine residues, including the irreversible aldehyde dehydrogenase (ALDH1A1) inhibitor disulfiram (Antabuse) [18]; the blockbuster proton pump inhibitors, e.g., omeprazole (Prilosec) and its single enantiomer esomeprazole (Nexium) [19]; inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) main protease by ebselen [20] and Paxlovid, and second-generation kinase inhibitors, e.g., afatinib (Gilotrif) [21]. Formation of covalent bonds to cysteines has also been shown to provide access to "undruggable" targets, as evidenced by Amgen's drug for KRAS G12C mutations, sotorasib. ...
Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “ S -XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S -XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S -XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S -XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1 G93A by S -XL6 that increases SOD1 G93A ’s in vivo half-life; and that S -XL6 crosses the blood–brain barrier. S -XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.
... There has been a correlation between cancer relapse and the expression of these ALDH enzymes in many human cancers (21). Compound 11 shows good inhibition against non-small cancer cells (IC 50 = A549: IC 50 = 3.91 μM, and leukaemia cell lines K562: IC 50 =1.91 ...
Multi-target-directed ligands (MTDL) or Designed Multiple Ligands (DML) use a single chemical substance to affect several ligands or targets associated with a disease to boost efficacy or safety. In recent studies, many novel quinolones have adapted this strategy by targeting many cancer ligands, including topoisomerase, tyrosine kinase, tubulin polymerisation, and formation of Gquadruplex. Moreover, the effectiveness of anticancer quinolones has been improved by the conjugation of compounds with metal complexes, such as ruthenium (III), boron, and copper (II). In the case of dual inhibitors, most of the substances target topoisomerases along with additional targets such as histone deacetylases, telomerase, microtubules, kinases, heat shock protein 90 (Hsp90), aldehyde dehydrogenase 1 (ALDH1) and proteasomes. Some of these hybrids, such as CX-5461, Q84441, and A-74441, have been shown to be effective against solid tumors with improved safety profiles. In this review, the current quinolone hybrids and DML strategy against a range of targets will be examined with the hope that the insights will aid in the development of novel quinolone derivatives for cancer treatment.
... Several studies demonstrated that ADH5 is involved in ethanol metabolism [32,33]. We also detected significant expression of ALDH1B, which is known to be localized in mitochondria like ALDH2 and is involved in acetaldehyde detoxification [34]. TK6 cells, therefore, would have the potential to metabolize ethanol. ...
Acetaldehyde, a chemical that can cause DNA damage and contribute to cancer, is prevalently present in our environment, e.g., in alcohol, tobacco, and food. Although aldehyde potentially promotes crosslinking reaction among biological substances including DNA, RNA, and proteins, it remains unclear what types of DNA damage are caused by acetaldehyde and how they are repaired. In this study, we examined acetaldehyde sensitivity of DNA damage-deficient cells established from human TK6 cell line. Among the mutants, mismatch repair mutants did not show a hypersensitivity to acetaldehyde, while cells deficient in base and nucleotide excision repair pathways increased its sensitivity. We found a delayed repair and hypersensitivity in homologous recombination (HR)-deficient cells but not in non-homologous end joining-deficient cells after acetaldehyde treatment. By analyzing the formation of acetaldehyde-induced RAD51 foci, which represent HR intermediates, HR-deficient cells, but not NHEJ, exhibits delayed repair of acetaldehyde-induced DNA damages, compared with wild-type. These results suggest that acetaldehyde causes complex DNA damages that requires various types of repair pathways. Interestingly, mutants deficient in TDP1 and TDP2, which are involved in the removal of protein adducts from DNA ends, exhibited hypersensitivity to acetaldehyde. the acetaldehyde sensitivity of the TDP1-/-/RAD54-/- double mutant was similar to that of each single mutant. This epistatic relationship between TDP1 and RAD54 suggests that that the removal of protein-DNA adducts generated by acetaldehyde needs to be removed for efficient repair by HR. Our study would help understand the molecular mechanism of genotoxic and mutagenic effects of acetaldehyde.
... The rate of ALDH produced in cells is regulated at transcriptional and post-transcriptional levels [42]. At the moment we may speculate that each isoform of ALDH undergoes unique quantitative adaptations to exposure to CSE constituents as ALDH family members display different substrate specificity [23]. So far it was demonstrated that CSE induces ALDH3A1 via aryl hydrocarbon receptor (AHR) [22]. ...
... ALDH2 is a well-researched non-cytochrome P450 mitochondrial aldehyde oxidizing enzyme synonymous with its role in the metabolism of acetaldehyde arising from ethanol consumption [3,6,28,29]. One of the most common genetic variations in ALDH2 is a single nucleotide polymorphism (SNP) that results in a Lys487->Glu (K487E) substitution (ALDH2 × 2 allele). ...
... To better treat cancer and combat treatment resistance, efforts have been made to specifically target the ALDHs [6]. In general, three structural domains can be distinguished in ALDH enzymes: the catalytic domain, the NAD(P)±binding domain, and the oligomerization domain [55]. ...
... The ALDH isoforms' homodimers and homotetramers are produced by the oligomerization domain. ALDH inhibitors can be divided into two groups: isoform-specific and multi-isoform [6]. ...
Aldehyde dehydrogenase (ALDH) is an important enzyme that metabolizes reactive
exogenous and endogenous aldehydes in the body through NAD(P)±dependent oxidation. Hence this
family of enzymes possess important physiological as well as toxicological roles in human body.
Significant efforts in the field have led to potent inhibitors with approved clinical agents for alcohol
use disorder therapy. Further clinical translation of novel compounds targeting ALDH inhibition will
validate the promised therapeutic potential in treating many human diseases.
... However, disulfiram inhibits ALDH1 more effectively than ALDH2 and it has a global inhibitory effect on ALDH2 [24,25]. In a variety of organs, ALDH2 protects tissues from damage by reducing oxidative stress and removing toxic aldehydes [26][27][28][29]. Daidzin is a naturally occurring product and is a specific inhibitor of ALDH2 (IC 50 = 0.08 µM) [30]. ...
Aldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and is acknowledged as a potential therapeutic target for the treatment of alcohol use disorder and other addictive behaviors. Using previously reported ALDH2 inhibitors of Daidzin, CVT-10216, and CHEMBL114083 as reference molecules, here we perform a ligand-based virtual screening of world-approved drugs via 2D/3D similarity search methods, followed by the assessments of molecular docking, toxicity prediction, molecular simulation, and the molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) analysis. The 2D molecular fingerprinting of ECFP4 and FCFP4 and 3D molecule-shape-based USRCAT methods show good performances in selecting compounds with a strong binding behavior with ALDH2. Three compounds of Zeaxanthin (q = 0), Troglitazone (q = 0), and Sequinavir (q = +1 e) are singled out as potential inhibitors; Zeaxanthin can only be hit via USRCAT. These drugs displayed a stronger binding strength compared to the reported potent inhibitor CVT-10216. Sarizotan (q = +1 e) and Netarsudil (q = 0/+1 e) displayed a strong binding strength with ALDH2 as well, whereas they displayed a shallow penetration into the substrate-binding tunnel of ALDH2 and could not fully occupy it. This likely left a space for substrate binding, and thus they were not ideal inhibitors. The MM–PBSA results indicate that the selected negatively charged compounds from the similarity search and Vina scoring are thermodynamically unfavorable, mainly due to electrostatic repulsion with the receptor (q = −6 e for ALDH2). The electrostatic attraction with positively charged compounds, however, yielded very strong binding results with ALDH2. These findings reveal a deficiency in the modeling of electrostatic interactions (in particular, between charged moieties) in the virtual screening via the 2D/3D similarity search and molecular docking with the Vina scoring system.
