Caspase inhibition switches doxorubicin-induced apoptosis to senescence

Rebbaa, Abdelhadi; Zheng, Xin; Chou, Pauline M.; Mirkin, Bernard L.

doi:10.1038/sj.onc.1206366

Cited by 167 publications

(131 citation statements)

References 32 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…At a higher doxorubicin concentration (10 À6 M), the cytotoxic response was apoptotic in nature as demonstrated by DNA fragmentation (Figure 1d). These findings and others from our laboratory 3 provide evidence that senescence and apoptosis are induced at distinct stress levels.…”

Section: Resultssupporting

confidence: 74%

“…This has been addressed by comparing the occurrence of DNA damage, expression of markers of proliferation arrest and extent of cell death in response to DNA-damaging and non-damaging drugs. The ability to distinguish between the stress levels required for senescence and apoptosis (Figures 1 and 2), 3,4 makes it possible to investigate whether DNA damage was part of the signaling pathway leading to one or the other of these cellular demises. If it associated with senescence, H2AX activation by a DNA-damaging drug must occur with lower or at least equivalent drug amounts to that required for the induction of p21/WAF1.…”

Section: Discussionmentioning

confidence: 99%

“…Reactive bands were detected by chemiluminescence. 3 Flow cytometry SKN-SH cells (about 10 6 ) were incubated with various concentrations of doxorubicin for 24 h, then collected by trypsinization and washed twice with PBS containing 5 mM EDTA. Cells were fixed in 70% ethanol and incubated for 10 min on ice.…”

Section: Western-blot Analysismentioning

confidence: 99%

“…During the last decade, the major focus of basic research was directed towards defining the molecular pathways of apoptosis and determination of their role in chemotherapy outcome, particularly since this form of cellular demise was believed to be a key factor in the development of drug resistance. 1 However, recent evidence indicates that the inhibition of apoptosis alone may not be sufficient for acquisition of the drug resistance phenotype [2][3][4] and that cancer cells not only have to be viable, but must be able to proliferate in order for the tumor to progress and develop a drug-resistant phenotype. Considering that cancer cell lines with deficiencies in the apoptotic pathway can still undergo proliferation arrest as a generalized response to drugs, achieving irreversible growth arrest would be sufficient for the control of cancer progression and the prevention of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis

et al. 2006

View full text Add to dashboard Cite

The present study was undertaken to determine the significance of histone acetylation versus DNA damage in drug-induced irreversible growth arrest (senescence) and apoptosis. Cellular treatment with the DNA-damaging drugs doxorubicin and cisplatin or with the histone deacetylase inhibitor trichostatin A, led to the finding that all the three drugs induced senescence at concentrations significantly lower than those required for apoptosis. However, only doxorubicin and cisplatin induced activation of H2AX, a marker for double-strand break formation. Interestingly, this occurred mainly at apoptosis and not senescence-inducing drug concentrations, suggesting that non-DNA-damage pathways may be implicated in induction of senescence by these drugs. In agreement with this, chromatin immunoprecipitation experiments indicated that doxorubicin was able to induce acetylation of histone H3 at the promoter of p21/WAF1 only at senescence-inducing concentrations. Collectively, these findings suggest that alteration of chromatin structure by cytotoxic drugs may represent a key mediator of senescence.

show abstract

Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Western-blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Interestingly it has been observed that the switch from a caspase-dependent to a 17 caspase-independent pathway allows the progression from a specific cell death state to another [40]. Jurkat cells treated with high concentrations of TQ likely switch to a particular cell death program which involves the p73-dependent CICD pathway.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

Alhosin

Abusnina

Achour

et al. 2010

Biochemical Pharmacology

130

116

View full text Add to dashboard Cite

The salvage anti-tumoral pathway which implicates the p53-related p73 gene is not yet fully characterized. We therefore attempted to identify the up-and down-stream events involved in the activation of the p73-dependent pro-apoptotic pathway, by focusing on the anti-apoptotic and epigenetic integrator UHRF1 which is essential for cell cycle progression. For this purpose, we analyzed the effects of a known anti-neoplastic drug, thymoquinone (TQ), on the p53-deficient acute lymphoblastic leukemia (ALL) Jurkat cell line. Our results showed that TQ inhibits the proliferation of Jurkat cells and induces G1 cell cycle arrest in a dose-dependent manner. Moreover, TQ treatment triggers programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (m). TQ-induced apoptosis, confirmed by the presence of hypodiploid G0/G1 cells, is associated with a rapid and sharp re-expression of p73 and dose-dependent changes of the levels of caspase-3 cleaved subunits. These modifications are accompanied by a dramatic down-regulation of UHRF1 and two of its main partners, namely DNMT1 and HDAC1, which are all involved in the epigenetic code regulation. Knockdown of p73 expression restores UHRF1 expression, reactivates cell cycle progression and inhibits TQ-induced apoptosis. Altogether our results showed that TQ mediates its growth inhibitory effects on ALL p53-mutated cells via the activation of a p73-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets UHRF1.

show abstract

The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging‐related disease

Marongiu

DeGregori

2022

Molecular Oncology

View full text Add to dashboard Cite

Aging represents the major risk factor for the development of cancer and many other diseases. Recent findings show that normal tissues become riddled with expanded clones that are frequently driven by cancer‐associated mutations in an aging‐dependent fashion. Additional studies show how aged tissue microenvironments promote the initiation and progression of malignancies, while young healthy tissues actively suppress the outgrowth of malignant clones. Here, we discuss conserved mechanisms that eliminate poorly functioning or potentially malignant cells from our tissues to maintain organismal health and fitness. Natural selection acts to preserve tissue function and prevent disease to maximize reproductive success but these mechanisms wane as reproduction becomes less likely. The ensuing age‐dependent tissue decline can impact the shape and direction of clonal somatic evolution, with lifestyle and exposures influencing its pace and intensity. We also consider how aging‐ and exposure‐dependent clonal expansions of “oncogenic” mutations might both increase cancer risk late in life and contribute to tissue decline and non‐malignant disease. Still, we can marvel at the ability of our bodies to avoid cancers and other diseases despite the accumulation of billions of cells with cancer‐associated mutations.

show abstract

Caspase inhibition switches doxorubicin-induced apoptosis to senescence

Cited by 167 publications

References 32 publications

The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis

The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging‐related disease

Contact Info

Product

Resources

About