Pro-senescence therapy for cancer treatment

Nardella, Caterina; Clohessy, John G.; Alimonti, Andrea; Pandolfi, Pier Paolo

doi:10.1038/nrc3057

Cited by 393 publications

(431 citation statements)

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“…Senescence has been shown to inhibit tumour progression in vivo 1 , thus the induction of senescence may represent a new alternative strategy to eradicate cancer 43 . Unfortunately, senescence usually relies on the activation of p53 and pRB tumour suppressor pathways that are often mutated or lost in tumours 44 , reducing the number of cancer types treatable by senescence induction.…”

Section: Resultsmentioning

confidence: 99%

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

et al. 2011

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senescence is triggered by various cellular stresses that result in genomic lesions and DnA damage response activation. However, the role of chromatin and DnA replication in senescence induction remains elusive. Here we show that downregulation of p300 histone acetyltransferase activity induces senescence by a mechanism that is independent of the activation of p53, p21 CIP1 and p16 InK4A . This inhibition leads to a global H3, H4 hypoacetylation, initiating senescence-associated heterochromatic foci formation during s phase, together with a global decrease in replication fork velocity, and alteration of DnA replication timing. This replicative stress occurs without DnA damage and checkpoint activation, but results in a robust G2/m cell cycle arrest, within only one cell cycle. These results provide new insights into the control of s-phase progression by p300, and identify an unexpected chromatindependent alternative mechanism for senescence induction, which could possibly be exploited to treat cancer by senescence induction without generating further DnA damage.

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Section: Resultsmentioning

confidence: 99%

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

et al. 2011

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“…Premature senescence is a major cellular response to chemotherapy and radiotherapy in solid tumors (6,7), and an intact senescence pathway critically contributes to the success of chemotherapy (8). Hence, the induction of senescence has been proposed as a potential strategy for therapeutic intervention in cancer (9,10). Senescent cells remain viable, metabolically active, and acquire a complex phenotype, including distinctive morphological alterations (flat and enlarged morphology), the expression of acidic ␤-galactosidase, and a specific increase in the secretion of cytokines, chemokines, and other factors, which has been termed the "senescence-associated secretory phenotype" or SASP 2 (11,12).…”

mentioning

confidence: 99%

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Crescenzi

Raia

Pacifico

et al. 2013

Journal of Biological Chemistry

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Background: Wip1 is a phosphatase involved in DNA-damage response. Results: Wip1 expression is down-regulated in premature senescent cancer cells. Failure to down-regulate Wip1 expression results in cell death and polyploidy. Conclusion: Wip1 down-regulation is important for maintenance of permanent cell cycle arrest in premature senescent tumor cells. Significance: These findings improve our understanding of the mechanism by which Wip1 promotes tumor progression.

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“…Accumulating evidence indicates that senescence plays an important role in the natural physiological response to tumor development [43] . Multiple pieces of evidence reveal that signaling events underlying the senescent phenotype, including, but not limited to, invasion, metastasis [44] , proliferation [45] …”

Section: Discussionmentioning

confidence: 99%

“…Nardella and Cairney et al proposed that these intrinsic senescence pathways can be used to specifically enhance senescence for the potential eradication of disease through targeted approaches [43,47] . Therefore, cancer cell senescence has become a new frontier for drug development.…”

Section: Wwwchinapharcom LI Y Et Almentioning

confidence: 99%

Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence

Han

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of 7 novel 1-ferrocenyl-2-(5-phenyl-1H-1,2,4-triazol-3-ylthio) ethanone derivatives on human lung cancer cells in vitro and to determine the mechanisms of action. Methods: A549 human lung cancer cells were examined. Cell viability was analyzed with MTT assay. Cell apoptosis and senescence were examined using Hoechst 33258 and senescence-associated-β-galactosidase (SA-β-gal) staining, respectively. LDH release was measured using a detection kit. Cell cycle was analyzed using a flow cytometer. Intracellular ROS level was measured with the 2′,7′-dichlorodihydrofluorescein probe. Phosphorylation of p38 was determined using Western blot. Results: Compounds 5b, 5d, and 5e (40 and 80 µmol/L) caused significant decrease of A549 cell viability, while other 4 compounds had no effect on the cells. Compounds 5b, 5d, and 5e (80 µmol/L) induced G 1 -phase arrest (increased the G 1 population by 22.6%, 24.23%, and 26.53%, respectively), and markedly increased SA-β-gal-positive cells. However, the compounds did not cause nuclear DNA frag mentation and chromatin condensation in A549 cells. Nor did they affect the release of LDH from the cells. The compounds significantly elevated the intracellular ROS level, decreased the mitochondrial membrane potential, and increased p38 phosphorylation in the cells. In the presence of the antioxidant and free radical scavenger N-acetyl-L-cysteine (10 mmol/L), above effects of compounds 5b, 5d, and 5e were abolished. Conclusion: The compounds 5b, 5d, and 5e cause neither apoptosis nor necrosis of A549 cells, but exert anti-cancer effect via inducing G 1 -phase arrest and senescence through ROS/p38 MAP-kinase pathway.

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Pro-senescence therapy for cancer treatment

Cited by 393 publications

References 100 publications

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence

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