Anastasis and Other Apoptosis-Related Prosurvival Pathways Call for a Paradigm Shift in Oncology: Significance of Deintensification in Treating Solid Tumors

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1881 - 1881

Published: Feb. 22, 2025

What is apoptosis? The Nomenclature Committee on Cell Death and numerous other pioneering cancer/p53 biologists use the terms "apoptosis" "cell death" interchangeably, disregard mind-numbing complexity heterogeneity that exists within a tumor (intratumor heterogeneity), contribution of polyploid giant cancer cells (PGCCs; root causes therapy resistance relapse) to this heterogeneity, then propose novel apoptosis-stimulating anticancer strategies. This shocking for following three reasons. First, clinical studies reported since 1990s have revealed increased apoptosis in solid tumors associated with diversity poor prognosis. Second, we known years dying (apoptotic) release panel secretions (e.g., via phoenix rising pathways) promote metastatic outgrowth. Third, over decade ago, it was demonstrated can recover from late stages (after formation apoptotic bodies) homeostatic process anastasis, resulting emergence aggressive variants. cell surface expression CD24 has recently been be preferentially enriched recovered (anastatic) exhibit tumorigenic properties. These related discoveries outlined herein call paradigm shift oncology focus strategies minimize occurrence treacherous tumor-repopulating events therapy-induced dormancy reactivation). They also raise an intriguing question: deregulated anastasis (rather than evasion apoptosis) hallmark cancer?

Language: Английский

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Seco-Duocarmycin SA in Aggressive Glioblastoma Cell Lines

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2766 - 2766

Published: March 19, 2025

Glioblastoma multiforme (GBM) is among the most lethal primary brain tumors and characterized by significant cellular heterogeneity resistance to conventional therapies. This study investigates efficacy of seco-duocarmycin SA (seco-DSA), a novel DNA alkylating agent. Initial investigations using colony formation assay revealed that seco-DSA exhibits remarkable potential with IC50 values lower than its natural DSA counterpart. Cell viability indicated LN18 cells showed markedly greater sensitivity T98G cells. Furthermore, achieved full cytotoxic effect within 8 h drug incubation in GBM cell lines. Although induced concentration-dependent increase apoptotic death, extent apoptosis did not fully account for observed decrease viability. Instead, treatment resulted cycle arrest S G2/M phases. These findings suggest seco-DSA’s cytotoxicity primarily due ability disrupt progression, though precise mechanisms action remain be established, further research needed. Proteomic analysis treated also indicates dysregulation proteins involved senescence, apoptosis, repair, alluding seco-DSA-induced as major mechanism disruption. Data are available via ProteomeXchange dataset identifier “PXD061023”. Our reports promote future exploration therapeutic potential, representing critical step toward developing more targeted effective GBM.

Language: Английский

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Arachidonic acid suppresses lung cancer cell growth and modulates lipid metabolism and the ERK/PPARγ signaling pathway

Lipids in Health and Disease, Journal Year: 2025, Volume and Issue: 24(1)

Published: March 27, 2025

Lung cancer remains the leading cause of cancer-related mortality worldwide, necessitating development new treatment strategies. Arachidonic acid (ARA), a polyunsaturated fatty acid, shows promise in therapy due to its potential anti-tumor effects, although role lung unclear. This study investigated effects and underlying mechanism ARA on A549 NCI-H1299 cells. In vitro assays were used assess cell viability, apoptosis, colony formation, lipid droplet changes cellular content. dose-dependently suppressed facilitated formation both lines. Network pharmacology analysis was performed identify gene targets pathways, uncovering 61 overlapping genes between targets, with mitogen-activated protein kinase 1 (MAPK1) emerging as key gene. Enrichment analyses suggested that might be mediated through metabolism extracellular signal-regulated (ERK)/peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. lines, inhibited decreased lipids. Immunoblotting further confirmed significantly increased ERK phosphorylation while reducing PPARγ synthase (FASN) levels. experiments using GW9662, antagonist, inhibiting impairs viability promotes apoptosis. Furthermore, vivo demonstrated reduced tumor size weight xenograft model, validating effects. The therapeutic agent for involve relevant pathways. A future exploring full mechanisms is needed.

Language: Английский

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Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression

Cancers, Journal Year: 2024, Volume and Issue: 16(13), P. 2319 - 2319

Published: June 25, 2024

Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type (EGFRwt) gene amplification and/or EGFRvIII activating mutation. EGFR-driven relies on thioredoxin (Trx) glutathione (GSH) antioxidant systems to withstand excessive production of reactive oxygen species (ROS). The impact EGFRwt or overexpression response a Trx/GSH co-targeting strategy unknown. In this study, we investigated context EGFR GBM. Auranofin reductase (TrxR) inhibitor, FDA-approved for rheumatoid arthritis. L-buthionine-sulfoximine (L-BSO) inhibits GSH synthesis by targeting glutamate–cysteine ligase catalytic (GCLC) enzyme subunit. We analyzed mechanisms cytotoxicity auranofin interaction between L-BSO U87MG, U87/EGFRwt, U87/EGFRvIII isogenic cell lines. ROS-dependent effects were assessed using N-acetylsteine. show that decreased TrxR1 activity increased ROS. vitality colony formation protein polyubiquitination through mechanisms, suggesting role ROS auranofin-induced three PARP-1 cleavage was associated with downregulation cells. Remarkably, combination induced significant depletion intracellular synergistic regardless overexpression. Nevertheless, molecular modulated different extent among exhibited prominent increase, P-AKT(Ser-473), AKT decrease along drastic downregulation. U87/EGFRwt displayed lower basal levels DNA damage compared U87MG Our study provides evidence vitro. Unraveling sensitivity EGFR-overexpressing cells alone, combination, supports rationale repurpose promising pro-oxidant treatment

Language: Английский

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Delineating three-dimensional behavior of uveal melanoma cells under anchorage independent or dependent conditions

Cancer Cell International, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 23, 2024

Abstract Background Although rare, uveal melanoma (UM) is a life-threatening malignancy. Understanding its biology necessary to improve disease outcome. Three-dimensional (3D) in vitro culture methods have emerged as tools that incorporate physical and spatial cues better mimic tumor turn deliver more predictive preclinical data. Herein, we comprehensively characterize UM cells under different 3D settings suitable model study cell behavior therapeutic intervention. Methods Six lines were tested two-dimensional (2D) 3D-culture conditions. For cultures, used anchorage-dependent (AD) where embedded or seeded on top of basement membrane extracts anchorage-free (AF) agarose pre-coated plates, ultra-low attachment hanging drops, with without methylcellulose. Cultures analyzed for multicellular structures (MCTs) development by phase contrast confocal imaging, wellbeing was assessed based viability, integrity, vitality, apoptotic features, DNA synthesis. Vascular endothelial growth factor (VEGF) production evaluated hypoxic conditions function analysis. Results cultured following developed MCTs shaped spheres. Regardless their sizes degree compaction, these spheres displayed an outer ring viable proliferating cells, core less cells. In contrast, maintained established several morphological adaptations. Some remained isolated rounded, formed multi-size irregular aggregates, adopted 2D-like flat appearance. These invariably conserved metabolic activity melanocytic markers (i.e., expression Melan A/Mart-1 HMB45). Notably, hypoxia, secrete VEGF compared 2D Conclusions Under environment, form sphere-like acquire attributes reminiscent abnormal vascularized solid tumors . manner exposed diverse populations response from enriched extracellular matrix proteins (ECM) highlighting the plasticity This provides platform UM. The integration such platforms explore mechanisms ECM-mediated resistance, metastatic abilities, test novel therapeutics anti-angiogenics immunomodulators) would benefit care.

Language: Английский

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Evaluation of the in vivo acute toxicity and in vitro genotoxicity and mutagenicity of synthetic β-carboline alkaloids with selective cytotoxic activity against ovarian and breast cancer cell lines

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Journal Year: 2024, Volume and Issue: 899, P. 503808 - 503808

Published: Aug. 10, 2024

Language: Английский

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Beta-lapachone has antiproliferative effects and modulates the lncRNAs expression on bladder cancer cell lines with different TP53 statuses

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Purpose α-Lapachona (aLAP) and β-lapachona (bLAP) are noteworthy anticancer naphthoquinones. The chemoresistance observed in bladder cancer represents a global health concern, with relation to mutations the TP53 gene alterations expression of long non-coding RNA (lncRNAs). This study evaluated effects aLAP bLAP on tumor cell lines different statuses. Methods Cytotoxicity was assessed using MTT reduction method migration by scratch assay while clonogenic survival cycle were through colony counting flow cytometry, respectively. lncRNAs (JHDM1D-AS1, SBF2-AS1, CDT-2132N18.2, RP11-363E7.4) JHDM1D RT-qPCR. Results demonstrated greater cytotoxicity than aLAP. Its inhibitory survival, migration, all related modulation expression. A lncRNA SBF2-AS1 RT4 cells, accompanied an increase RP11-363E7.4. Conversely, cells mutated (J82), JHDM1D-AS1 observed. Conclusion antiproliferative independent statuses, yet occur distinct action mechanism, variations

Language: Английский

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