Targeting apoptotic pathways for cancer therapy

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(14)

Опубликована: Июль 14, 2024

Apoptosis is a form of programmed cell death that mediated by intrinsic and extrinsic pathways. Dysregulation resistance to are hallmarks cancer. For over three decades, the development therapies promote treatment cancer inducing various modalities, including apoptosis, has been main goal clinical oncology. pathways also interact with other signaling mechanisms, such as p53 pathway integrated stress response (ISR) pathway. In addition agents directly targeting components, anticancer drugs target ISR actively being developed. this Review, we discuss selected promising in stages development, drug targets, related treatments, focusing especially on B lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, strategies p53, mutant ISR.

Язык: Английский

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Mitochondrial stress: a key role of neuroinflammation in stroke

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Фев. 6, 2024

Abstract Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as pivotal event contributing to neuronal cell death. The occurrence and progression entail intricate processes, prominently featuring mitochondrial dysfunction adaptive responses. Mitochondria, double membrane-bound organelle are recognized “energy workshop” body. Brain particularly vulnerable disturbances due its high energy demands from mitochondria-related production. interplay between mitochondria plays significant role in pathogenesis stroke. biological pathological consequences resulting stress have substantial implications for function. Mitochondrial serves mechanism aimed at mitigating induced import misfolded proteins, which occurs response This involves reduction protein accumulation overall synthesis. influence on state stroke underscored capacity interact with neuroinflammation. impact varies according severity. Moderate can bolster cellular defenses, enabling cells better withstand detrimental stressors. contrast, sustained excessive detrimentally affects tissue integrity. relationship depends degree present. Understanding instrumental excavating novel treatment review aims provide evaluation cross-talk within context We aim reveal how environment

Язык: Английский

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Nicotinamide riboside intervention alleviates hematopoietic system injury of ionizing radiation‐induced premature aging mice

Aging Cell, Год журнала: 2023, Номер 22(11)

Опубликована: Авг. 31, 2023

Abstract Radiotherapy destroys cancer cells and inevitably harms normal human tissues, causing delayed effects of acute radiation exposure (DEARE) accelerating the aging process in most survivors. However, effective methods for preventing premature induced by ionizing are lacking. In this study, mice DEARE model was established after 6 Gy total body irradiation (TBI). Then therapeutic mechanism nicotinamide riboside on were evaluated. The results showed that TBI hematopoietic system mice. Nicotinamide treatment reversed spleen phenotypes inhibiting cellular senescence ameliorated serum metabolism profiles. Further demonstrated supplementation alleviated myeloid bias stem temporarily restored regenerative capacity probably mitigating reactive oxygen species activated GCN2/eIF2α/ATF4 signaling pathway. study firstly indicate shows potential as a agent radiation‐exposed populations patients who received radiotherapy.

Язык: Английский

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Repurposing peripheral immunocytes of Bacillus Calmette Guerin-vaccinated melanoma patients to reveal preventive Alzheimer's disease mechanisms, possibly via the unfolded protein response

Journal of Alzheimer s Disease Reports, Год журнала: 2025, Номер 9

Опубликована: Янв. 1, 2025

Background Alzheimer's disease (AD) dysfunctional unfolded protein response (UPR) is revealed by amyloid-β aggregates. Normally, UPR reacts to endoplasmic reticulum stress resolving misfolded/aggregated proteins, and failure induces brain-cell apoptosis consistent with AD pathology. Peripheral blood mononuclear cells (PBMC) immunocyte brain infiltrates are involved in pathogenesis, whose risk lowered the Bacillus Calmette Guerin (BCG) vaccine. Hypothetically, BCG prevents caused UPR-driven PBMC infiltrates, corrected BCG-vaccinated infiltrates. Objective To reveal whether shifts towards cell survival. Method: proteins from 6 individuals were compared immuno-electrophoresis before after hypervaccination. Cryopreserved provided an opportunity analyze impact on UPR, although their donor destiny develop was unknown. signaling responsive recorded examine if can influence thereby explain previously demonstrated prevention BCG. Results signal levels scored according positive versus negative survival odds a dozen signals. The balance between scores of emphasizes vaccine UPR. antiapoptotic signals under show opposite trends brains, reported literature. In conclusion, 3/6 had superior chances Conclusions These results suggest that part mechanism responsible for reducing AD, as shown among BCG-treated bladder cancer patients.

Язык: Английский

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Unraveling the Binding Mode of TSC2–Rheb through Protein Docking and Simulations

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

Proteasome inhibitors (PIs) constitute the first line of therapy for multiple myeloma (MM). Despite impressive clinical efficacy, MM remains fatal due to development drug resistance over time. During progression, stress responses hypoxia and PIs suppress mammalian target rapamycin complex 1 (mTORC1) activity by releasing tuberous sclerosis 2 (TSC2), which deactivates Ras homologue enriched in brain (Rheb), a crucial regulator mTORC1. The efficacy targeting is enhanced when mTORC1 hyperactivated. We thus propose that inhibition TSC2 will improve MM. To best our knowledge, no cocrystallized structure TSC2–Rheb has been reported. therefore developed representative model using individual structures (PDB: 7DL2) Rheb 1XTS). Computational modeling involving an extensive protein–protein docking consensus approach was performed determine putative binding mode TSC2–Rheb. proposed poses were refined, clustered, evaluated MD simulations explore conformational dynamics protein mobility, particularly at drug-binding interface Our results agree with suggested previously reported literature. herein establish basis new blocking Rheb, aiming reinstate activation facilitate improved against myeloma.

Язык: Английский

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The Antitumor Effects and Apoptotic Mechanism of 20(S)-Protopanaxadiol in Acute Myeloid Leukemia

Journal of Ginseng Research, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress.

PubMed, Год журнала: 2023, Номер 22, С. 520 - 555

Опубликована: Янв. 1, 2023

As a requirement of aerobic metabolism, regulation redox homeostasis is indispensable for the continuity living and life. Since stability state necessary maintenance biological functions cells, balance between pro-oxidants, especially ROS antioxidant capacity kept in cells through defense systems. The pleiotropic transcription factor, Nrf2, master regulator system. Disruption leads to oxidative reductive stress, bringing about multiple pathophysiological conditions. Oxidative stress characterized by high levels causes damage biomolecules cell death, while low disrupt physiological functions. fact that ROS, which were initially attributed as harmful products at same time function signal molecules non-toxic play role adaptive response called mithormesis points out have dose-dependent effect on fate determination. See also Figure 1(Fig. 1).

Язык: Английский

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Multiple roles for AU-rich RNA binding proteins in the development of haematologic malignancies and their resistance to chemotherapy

RNA Biology, Год журнала: 2024, Номер 21(1), С. 584 - 600

Опубликована: Май 27, 2024

Post-transcriptional regulation by RNA binding proteins can determine gene expression levels and drive changes in cancer cell proteomes. Identifying mechanisms of protein-RNA binding, including preferred sequence motifs bound

Язык: Английский

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Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα–JNK pathway

Cancer Gene Therapy, Год журнала: 2024, Номер 31(10), С. 1486 - 1497

Опубликована: Авг. 9, 2024

Arsenic trioxide (ATO) has exhibited remarkable efficacy in treating acute promyelocytic leukemia (APL), primarily through promoting the degradation of PML-RARα fusion protein. However, ATO alone fails to confer any survival benefit non-APL myeloid (AML) patients and exhibits limited when used combination with other agents. Here, we explored general toxicity mechanisms APL potential drugs that could be combined exhibit synergistic lethal effects on AML. We demonstrated ROS upregulation were insufficient cause cell death. Based protein synthesis different AML cells their sensitivity ATO, established a correlation between ATO-induced death synthesis. Our findings indicated induced by damaging nascent polypeptides causing ribosome stalling, accompanied activation ZAKα-JNK pathway. Furthermore, stress activated GCN2–ATF4 pathway, ribosome-associated quality control cleared damaged proteins assistance p97. Importantly, our data revealed inhibiting p97 enhanced effectiveness killing cells. These explorations paved way for identifying optimal synthetic enhance treatment

Язык: Английский

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Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

ABT-199 (venetoclax) is a BCL-2 suppressor with pronounced effects on acute myeloid leukemia (AML). However, its usefulness as monotherapy or in combination hypomethylating medicines like azacitidine debatable due to acquired resistance. Usnic acid, dibenzofuran extracted from lichen Usnea diffracta Vain, exhibits anticancer properties and may counteract multidrug resistance cells.

Язык: Английский

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