Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine DOI Creative Commons
Mahesh Tambe, S. Herbert Unterberger,

Mette C. Kriegbaum

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(10)

Published: Oct. 16, 2024

Abstract Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the rarely curative, relapse due to resistant disease eventually emerges. Since no current feasible treatments are known be effective at state of acquired venetoclax resistance, this becoming a major challenge in AML treatment. Studying venetoclax-resistant cell lines, we observed that induced sublethal apoptotic signaling DNA damage even though survival growth were unaffected. This effect could inducing degree mitochondrial outer membrane permeabilization. Based on these results, hypothesized by constitute vulnerability cells. was supported screens with broad collection drugs, where synergistic between PARP inhibition Additionally, venetoclax-PARP inhibitor combination prevented acquisition resistance naïve lines. Furthermore, addition enhanced exhibited exceptional sensitivity long-term responses lines samples from patients had relapsed under venetoclax-azacitidine therapy. In conclusion, mechanistically identify new cells as potential therapeutic approach overcome AML.

Language: Английский

Crosstalk between mitochondria–ER contact sites and the apoptotic machinery as a novel health meter DOI Creative Commons

Alvaro Larrañaga-SanMiguel,

Nora Bengoa‐Vergniory, Hector Flores‐Romero

et al.

Trends in Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

Citations

7
Cell death: Revisiting the roads to ruin DOI Creative Commons
Douglas R. Green

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(19), P. 2523 - 2531

Published: Oct. 1, 2024

A paradigm shift in the study of cell death is currently occurring: whereas previously we had always considered that there were "points no return" any pathway, now realize many types active, regulated death, this not case. We are also learning cells "almost die," but nevertheless survive, can transiently take on an altered state, with potential implications for understanding cancer therapies and relapse. In perspective, parse forms by analogy to suicide, sabotage, murder, consider how might be "instructed" engage a pathway survive.

Language: Английский

Citations

6
MOMP: A critical event in cell death regulation and anticancer treatment DOI
Dan Liu, Ziqi Liu, Hu Yan

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 189280 - 189280

Published: Feb. 1, 2025

Language: Английский

Citations

0
Defeating lethal cancer: Interrupting the ecologic and evolutionary basis of death from malignancy DOI Open Access
Kenneth J. Pienta,

Patrick L. Goodin,

Sarah R. Amend

et al.

CA A Cancer Journal for Clinicians, Journal Year: 2025, Volume and Issue: unknown

Published: March 9, 2025

Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved survival, globally, there is an increased incidence cancer-related deaths. Although each patient tumor wholly unique, tipping point incurable disease common across patients: dual capacity for cancers metastasize resist systemic treatment. The discovery genetic mutations epigenetic variation that emerges during progression highlights evolutionary ecology principles can be used understand how evolves a lethal phenotype. By applying such eco-evolutionary framework, authors reinterpret our understanding metastatic process as one ecologic invasion define paths evolving therapy resistance. With this understanding, draw from successful strategies optimized strategic interventions with goal altering trajectory cancer. Ultimately, studying, treating using provides opportunity improve lives patients

Language: Английский

Citations

0
The BCL-2 protein family: from discovery to drug development DOI Creative Commons
Carlo M. Croce, David L. Vaux, Andreas Strasser

et al.

Cell Death and Differentiation, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Abstract The landmark discovery of the BCL-2 gene and then its function marked identification inhibition apoptotic cell death as a crucial novel mechanism driving cancer development launched quest to discover molecular control apoptosis. This work culminated in generation specific inhibitors that are now clinical use, saving improving tens thousands lives annually. Here, some original players this story, describe sequence critical discoveries. t(14;18) chromosomal translocation, frequently observed follicular lymphoma, allowed cloning oncogene ( ) juxtaposed immunoglobulin heavy chain locus IgH ). Of note, acted distinct manner compared already known oncogenic proteins like ABL c-MYC. did not promote proliferation but inhibited death, originally shown growth factor dependent haematopoietic progenitor lines (e.g., FDC-P1) Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following rapid expansion protein family, Abbott Laboratories solved first structure BCL-XL subsequently BCL-XL/BAK peptide complex, opening way understanding structures other family members and, finally, different pro-survival proteins, thanks efforts Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude Gilead. Although inhibitor Venetoclax is use MCL-1 undergoing trials, several questions remain on whether therapeutic windows can be achieved what agents should used combination with BH3 mimetics achieve optimal impact for therapy. Finally, expression BH3-only needs better understood may identify targets story still concluded!

Language: Английский

Citations

0
Kinase signalling adaptation supports dysfunctional mitochondria in disease DOI Creative Commons
George Skalka,

Mina Tsakovska,

Daniel J. Murphy

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 26, 2024

Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation mitochondria as driver in cancer. However, pathways support and promote this adapted mitochondrial function? A key hallmark cancer is perturbation kinase signalling pathways. These include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated (AMPK), Ca 2+ /calmodulin-dependent (CaMK) networks. multiple substrates initiation persistence Many these involved the regulation morphology, apoptosis, calcium homeostasis, associated membranes (MAMs), retrograde ROS signalling. This review will aim to both explore how integrates with highlight systems can be usurped development disease. In addition, we identify areas require further investigation fully understand complexities regulatory interactions. Overall, emphasize studying interaction between improves our understanding homeostasis yield novel therapeutic targets treat

Language: Английский

Citations

3
GluOC promotes proliferation and metastasis of TNBC through the ROCK1 signaling pathway DOI Creative Commons
Jiaojiao Xu,

Keting Dong,

Xue Bai

et al.

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

Published: July 25, 2024

Abstract Background Triple negative breast cancer (TNBC) is a type of that for oestrogen receptor, progesterone receptor and human epidermal growth factor 2, highly malignant aggressive, lacks corresponding targeted therapy, has relatively poor prognosis. Therefore, understanding the mechanism TNBC development formulating effective treatment strategies inducing cell death are still urgent tasks in TNBC. Research shown uncarboxylated osteocalcin can promote proliferation prostate cancer, lung adenocarcinoma cells, but by which GluOC affects metastasis needs further study. Methods MDA-MB-231 cells were used vitro analysis. Key target molecules or pathways identified RNA sequencing, migration ability was detected scratch assays, Transwell adhesion assays western blot Fluorescence staining, colony detection, qRT‒PCR flow cytometry to detect apoptosis, oxidative stress, cycle stemness xenotransplantation model BALB/C nude mice vivo Results This study demonstrated facilitates through ROCK1/MYPT1/MLC2 signalling pathway promotes via ROCK1/JAK2/PIK3CA/AKT pathway. Experiments promoted tumour tumour-bearing mice, clarified molecular invasion. Conclusion Our findings highlight importance driving progression its association with patient outcomes. clarifies functional effects on growth, providing insight into basis potentially new ideas developing therapies improve

Language: Английский

Citations

3
Not dead yet: cell death and survival in cancer and normal physiology DOI Creative Commons
Douglas R. Green

Frontiers in Cell Death, Journal Year: 2024, Volume and Issue: 3

Published: Sept. 11, 2024

For decades, we have assumed that all regulated cell death pathways a dedicated “point of no return” precedes but after which cells are committed to die. The realization this is often not the case represents what can be considered paradigm shift in field. Here consider how survive despite engagement pathway and consequences “near experience” cancer possibly other physiological conditions.

Language: Английский

Citations

2
TRAIL-induced apoptosis and proteasomal activity – Mechanisms, signalling and interplay DOI
Chiara Boccellato, Markus Rehm

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2024, Volume and Issue: 1871(4), P. 119688 - 119688

Published: Feb. 16, 2024

Language: Английский

Citations

1
Lethal and sublethal effects of programmed cell death pathways on hematopoietic stem cells DOI Creative Commons
Yuta Yamada, Zhiqian Zheng,

Alaa K. Jad

et al.

Experimental Hematology, Journal Year: 2024, Volume and Issue: 134, P. 104214 - 104214

Published: April 4, 2024

Programmed cell death is an evolutionally conserved cellular process in multicellular organisms that eliminates unnecessary or rogue cells during development, infection, and carcinogenesis. Hematopoietic stem (HSCs) are a rare, self-renewing, multipotent population necessary for the establishment regeneration of hematopoietic system. Counterintuitively, key components programmed induction abundantly expressed long-lived HSCs, which often survive myeloablative stress by engaging prosurvival response counteracts death-inducing stimuli. Although HSCs well known their apoptosis resistance, recent studies have revealed unique vulnerability to certain types necrosis, such as necroptosis ferroptosis. Moreover, emerging evidence has shown pathways can be sublethally activated cause nonlethal consequences innate immune response, organelle dysfunction, mutagenesis. In this review, we summarized findings on how divergent programs molecularly regulated HSCs. We then discussed potential side effects caused sublethal activation functionality surviving

Language: Английский

Citations

1