ALDH and cancer stem cells: Pathways, challenges, and future directions in targeted therapy

Life Sciences, Journal Year: 2024, Volume and Issue: 356, P. 123033 - 123033

Published: Aug. 31, 2024

Language: Английский

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Cancer Stem Cells in Renal Cell Carcinoma: Origins and Biomarkers

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13179 - 13179

Published: Aug. 24, 2023

The term "cancer stem cell" (CSC) refers to a cancer cell with the following features: clonogenic ability, expression of markers, differentiation into cells different lineages, growth in nonadhesive spheroids, and vivo ability generate serially transplantable tumors that reflect heterogeneity primary cancers (tumorigenicity). According this model, CSCs may arise from normal cells, progenitor and/or differentiated because striking genetic/epigenetic mutations or fusion tissue-specific circulating bone marrow (BMSCs). use signaling pathways similar those controlling fate during early embryogenesis (Notch, Wnt, Hedgehog, morphogenetic proteins (BMPs), fibroblast factors, leukemia inhibitory factor, transforming factor-β). Recent studies identified subpopulation CD133+/CD24+ ccRCC specimens displayed self-renewal multipotency. development agents targeting CSC signaling-specific not only surface ultimately become utmost importance for patients RCC.

Language: Английский

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ALDH1A1 in breast cancer: A prospective target to overcome therapy resistance (Review)

Oncology Letters, Journal Year: 2025, Volume and Issue: 29(5), P. 1 - 17

Published: March 4, 2025

The expression of cytosolic aldehyde dehydrogenases (ALDHs), which mediate the last step in pathway synthesis all‑trans retinoic acid, is dysregulated various types human cancer, and has been associated with development cancer stem cells (CSCs) solid tumors hematological malignancies. CSCs are considered a minor fraction capacity to initiate neoplastic tumors. ALDH1A1 serves crucial role emergence CSC phenotype, induces malignant behavior promotes treatment resistance. Notably, ALDH1A1‑induced therapy resistance not exclusive just one group drugs, but affects diverse drugs that use different mechanisms kill cells. This diversity drug resistance‑inducing effects stemness‑supporting functions ALDH1A1. inhibition activity using chemicals or depletion via genetic approaches, such as small interfering RNA, can overcome pathways In context breast it critical only expected manifest stem‑like features, include increased From angle disease prognosis, extent association remains be determined through application cutting‑edge methods detect tracked biomarkers within

Language: Английский

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Identification of approved drugs with ALDH1A1 inhibitory potential aimed at enhancing chemotherapy sensitivity in cancer cells: an in-silico drug repurposing approach

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 15

Published: Jan. 8, 2024

The aldehyde dehydrogenase 1A1 (ALDH1A1) also known as retinal dehydrogenase, is an enzyme normally involved in the cellular metabolism, development and detoxification processes healthy cells. However, it's considered a cancer stem cell marker its high levels of expression several cancers, including breast, lung, ovarian, colon have been associated with poor prognosis resistance to chemotherapy. Given crucial role chemotherapy by chemotherapeutic drugs, ALDH1A1 has attracted significant research interest potential therapeutic target for cancer. Though few synthetic inhibitors synthesized their efficacy proved in-vitro in-vivo studies, none them passed clinical trials so far. In this scenario, we performed in-silico study verify whether any already approved drugs used various purposes ability inhibit catalytic activity ALDH1A1, that they can be repurposed therapy. Keeping mind feasibility repurposing larger population selected from five widely drug categories such antibiotic, antiviral, antifungal, anti diabetic antihypertensive screening. Computational techniques like molecular docking, dynamics simulations MM-PBSA binding energy calculation screen drugs. Based on logical analysis results, propose three – telmisartan, irbesartan maraviroc thus increase sensitivity

Language: Английский

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Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: April 24, 2024

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. latter is the main stemness mediator via enhancing signaling pathways Wnt/β-catenin, phosphatidylinositol 3-kinase/AKT, hypoxia. Furthermore, ALDH1A1 mediates therapeutic resistance inactivating drugs, stimulating expression drug efflux transporters, detoxifying reactive radical species, thereby apoptosis arresting. Recent reports disclosed potent broad-spectrum anticancer activities unique nanocomplexes diethyldithiocarbamate (DE, inhibitor) with ferrous oxide nanoparticles (FeO NPs) inducing lipid peroxidation-dependent non-apoptotic (iron accumulation-triggered ferroptosis), was reported. Accordingly, anti-stemness activity (DE-FeO investigated against human mouse glioma (GSCs) radioresistant GSCs (GSCs-RR). DE-FeO NPs exhibited strongest growth inhibition effect on treated (MGG18 JX39P), (GS PDGF-GSC) (IC 50 ≤ 70 161 μg/mL, respectively). also revealed higher inhibitory impact than standard chemotherapy (temozolomide, TMZ) self-renewal, cancer repopulation, chemoresistance, potentials. Besides, surpassed TMZ regarding relative all studied genes, as well p-AKT/AKT ratio in MGG18, GS (MGG18-RR GS-RR). This influence primarily attributed ferroptosis induction, confirmed significant elevation cellular oxygen species peroxidation depletion glutathione peroxidase 4. recorded optimal Log P value crossing blood brain barrier. vitro novel study declared potency collapsing GSCs-RR improving sensitivity radiotherapy, indicating that may be promising remedy GBM. Glioma animal models will needed in-depth studies its safe effectiveness.

Language: Английский

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Synergistic eradicating impact of 5-fluouracil with FeO nanoparticles-diethyldithiocarbamate in colon cancer spheroids

Nanomedicine, Journal Year: 2024, Volume and Issue: 19(11), P. 979 - 994

Published: April 5, 2024

Background: Cancer stem cells' (CSCs) resistance to 5-fluorouracil (Fu), which is the main obstacle in treating colon cancer (CC), can be overcome by ferroptosis. The latter, herein, triggered FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate-inhibited glutathione system aldehyde dehydrogenase (ALDH1A1-maintained stemness, therapeutic metastasis). Materials & methods: Nanocomplex diethyldithiocarbamate (FD) was used combination with Fu investigate its potential synergistic anti-CSC influence using CC spheroid models. Results: In + FD-treated spheroids, strongest growth inhibition, highest cell death percentage, lowest CD133+-CSCs percentage stemness gene expressions (e.g., drug efflux transporter), antimetastatic effect were recorded high indexes. Conclusion: FD represents effective therapy for chemoresistant cells.

Language: Английский

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Aldehyde dehydrogenase 1 family: A potential molecule target for diseases

Cell Biology International, Journal Year: 2024, Volume and Issue: 48(7), P. 909 - 922

Published: May 27, 2024

Abstract Aldehyde dehydrogenase 1 (ALDH1), a crucial aldehyde metabolizing enzyme, has six family members. The ALDH1 is expressed in various tissues, with significant presence the liver. It plays momentous role several pathophysiological processes, including detoxification, oxidative stress, and lipid peroxidation. Acetaldehyde detoxification fundamental function of participating vital pathological mechanisms. can catalyze retinal to retinoic acid (RA) that hormone‐signaling molecule development adult tissues. Furthermore, there need for further broader research on as signaling molecule. widely recognized cancer stem cell (CSC) marker proliferation, invasion, metastasis, prognosis, drug resistance cancer. also participates other human diseases, such neurodegenerative osteoarthritis, diabetes, atherosclerosis. inhibit disease progression by inhibiting/promoting expression/activity family. In this review, we comprehensively analyze tissue distribution, functions Additionally, review involvement focusing underlying mechanisms briefly talk about current status inhibitors. presents new possibilities treating both its upstream downstream pathways serving promising targets therapeutic intervention. This offers fresh perspectives field research.

Language: Английский

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Inhibition of Cancer Stem-like Cells by Curcumin and Other Polyphenol Derivatives in MDA-MB-231 TNBC Cells

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7446 - 7446

Published: July 6, 2024

Triple-negative breast cancer (TNBC) accounts for 15% of all cancers and is highly aggressive. Despite an initial positive response to chemotherapy, most patients experience rapid disease progression leading relapse metastasis. This attributed the presence stem cells (BCSCs) within tumor, which are characterized by self-renewal, pluripotency, resistance mechanisms. Targeting BCSCs has become critical as conventional therapies fail eradicate them due a lack specific targets. Curcumin, polyphenol derived from turmeric (Curcuma longa), exhibits anticancer effects against BCSCs. The use curcumin derivatives been suggested approach overcome bioavailability solubility problems in humans, thereby increasing its effects. aim this study was evaluate cellular molecular six synthetic compounds natural epigallocatechin gallate (EGCG) (TL1, TL2) (TL3, TL4, TL5, TL6) on TNBC mesenchymal stem-like cell line. activity also determined mammosphere inhibition assay studying different BCSC markers Western blotting. Finally, drug combination performed with promising their potential synergistic chemotherapeutic agents doxorubicin, cisplatin, paclitaxel. results showed that exhibited cytotoxicity line Interestingly, derivative TL3 doxorubicin cisplatin displayed effect cells.

Language: Английский

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A comparative study of smart nanoformulations of diethyldithiocarbamate with Cu4O3 nanoparticles or zinc oxide nanoparticles for efficient eradication of metastatic breast cancer

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: March 2, 2023

Abstract Metastatic tumor is initiated by metastatic seeds (cancer stem cells “CSCs”) in a controlled redox microenvironment. Hence, an effective therapy that disrupts balance with eliminating CSCs critical. Diethyldithiocarbamate (DE) potent inhibitor of radical detoxifying enzyme (aldehyde dehydrogenase “ALDH”1A) causing eradication CSCs. This DE effect was augmented and more selective its nanoformulating green synthesized copper oxide (Cu 4 O 3 ) nanoparticles (NPs) zinc NPs, forming novel nanocomplexes CD NPs ZD respectively. These exhibited the highest apoptotic, anti-migration, ALDH1A inhibition potentials M.D. Anderson-metastatic breast (MDA-MB) 231 cells. Importantly, these revealed oxidant activity than fluorouracil elevating reactive oxygen species depleting glutathione only tissues (mammary liver) using mammary liver metastasis animal model. Due to higher tumoral uptake stronger had potential induce apoptosis, suppress hypoxia-inducing factor gene, eliminate CD44 + downregulating their stemness, chemoresistance, genes diminishing hepatic marker (α-fetoprotein). interpreted size reduction complete eradicating NPs. Consequently, nanocomplex therapeutic representing safe promising nanomedicine against stage cancer.

Language: Английский

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Molecular Biomarkers and Signaling Pathways of Cancer Stem Cells in Colorectal Cancer

Technology in Cancer Research & Treatment, Journal Year: 2024, Volume and Issue: 23

Published: Jan. 1, 2024

Colorectal cancer (CRC) is the third most frequently found in world, and it discovered when already far along its development. About 20% of cases CRC are metastatic incurable. There more evidence that colorectal stem cells (CCSCs), which charge tumor growth, recurrence, resistance to treatment, what make so different. Because we know about cell biology, quickly learned molecular processes possible cross-talk between signaling pathways affect balance gut cancer. Wnt, Notch, TGF-β, Hedgehog examples pathway members whose genes may change produce CCSCs. These control self-renewal pluripotency SCs then decide function phenotype However, terms their ability create tumors susceptibility chemotherapeutic drugs, CSCs differ from normal bulk cells. This be reason for higher rate recurrence patients who underwent both surgery chemotherapy treatment. Scientists have a group uncontrolled miRNAs related CCSCs stemness properties. CCSC functions like changing expression cycle genes, metastasis, drug mechanisms. CCSC-related mostly signal known important biology. The biomarkers (CD markers miRNA) diagnostic roles main topics this review study.

Language: Английский

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