Senolytic targets and new strategies for clearing senescent cells

Ge, Ming-Xia; Hu, Li; Ao, Hong-Shun; Zi, Meiting; Kong, Qing‐Peng; He, Yonghan

doi:10.1016/j.mad.2021.111468

Cited by 39 publications

(33 citation statements)

References 97 publications

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“…Until now, several classes of senolytics have been developed, including naturally occurring compounds and their derivatives [e.g., quercetin ( Zhu et al, 2015 ), fisetin ( Yousefzadeh et al, 2018 ), piperlongumine ( Wang et al, 2016 ), EF24 ( Li et al, 2019a )], cardiac glycosides [e.g., ouabain ( Guerrero et al, 2019 ), digoxin ( Triana-Martínez et al, 2019 )], and targeted therapeutics [dasatinib ( Zhu et al, 2015 ), ABT263 ( Chang et al, 2016 ), HSP90 inhibitor ( Fuhrmann-Stroissnigg et al, 2017 ), and FOXO4-p53 interfering peptide ( Baar et al, 2017 )] ( Table 1 ). We have previously reviewed the progresses on naturally occurring and targeted senolytics ( Li et al, 2019b ; Ge et al, 2021 ). It is very encouraging that several senolytics have been approved to enter clinical trials and shown benefits as therapeutics for aging or age-related diseases ( Childs et al, 2017 ; Kirkland and Tchkonia, 2017 , 2020 ; Campisi et al, 2019 ; Thoppil and Riabowol, 2019 ; Di Micco et al, 2021 ).…”

Section: Targeting Senescent Cells With Senolytics and New Strategiesmentioning

confidence: 99%

“…Its on-target toxicity of thrombocytopenia induced by Bcl-xL inhibition prevents its use in clinic even for tumor patients ( Gandhi et al, 2011 ; Souers et al, 2013 ; Leverson et al, 2015 ; Ashkenazi et al, 2017 ). To overcome these challenges, some novel strategies, such as proteolysis-targeting chimera (PROTAC) technology ( He et al, 2020b ), chimeric antigen receptor (CAR) T cells ( Amor et al, 2020 ), and β-galactosidase-modified prodrugs ( Cai et al, 2020 ; Guerrero et al, 2020 ), have been developed to eliminate SnCs and shown promising therapeutic potential in the treatment of age-related diseases ( Ge et al, 2021 ).…”

Section: Targeting Senescent Cells With Senolytics and New Strategiesmentioning

confidence: 99%

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Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development

et al. 2022

Front. Cell Dev. Biol.

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Cellular senescence is a process that leads to a state of irreversible cell growth arrest induced by a variety of intrinsic and extrinsic stresses. Senescent cells (SnCs) accumulate with age and have been implicated in various age-related diseases in part via expressing the senescence-associated secretory phenotype. Elimination of SnCs has the potential to delay aging, treat age-related diseases and extend healthspan. However, once cells becoming senescent, they are more resistant to apoptotic stimuli. Senolytics can selectively eliminate SnCs by targeting the SnC anti-apoptotic pathways (SCAPs). They have been developed as a novel pharmacological strategy to treat various age-related diseases. However, the heterogeneity of the SnCs indicates that SnCs depend on different proteins or pathways for their survival. Thus, a better understanding of the underlying mechanisms for apoptotic resistance of SnCs will provide new molecular targets for the development of cell-specific or broad-spectrum therapeutics to clear SnCs. In this review, we discussed the latest research progresses and challenge in senolytic development, described the significance of regulation of senescence and apoptosis in aging, and systematically summarized the SCAPs involved in the apoptotic resistance in SnCs.

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Section: Targeting Senescent Cells With Senolytics and New Strategiesmentioning

confidence: 99%

Section: Targeting Senescent Cells With Senolytics and New Strategiesmentioning

confidence: 99%

Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development

et al. 2022

Front. Cell Dev. Biol.

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“…The effects of senescence and SASP are “erosive.” Once it starts, it has the potential to spread via the flowing cytokines to induce secondary senescence in the remote. Elimination of senescent cells by senolytic drugs has been proven to be effective to counteract senescence in natural aging or age-related disease model ( Kirkland and Tchkonia, 2017 ; Ge et al, 2021 ). Recently, the first clinical trial of senolytic drug was conducted in human with IPF.…”

Section: Conclusion and Future Directionmentioning

confidence: 99%

Dynamic Aging: Channeled Through Microenvironment

et al. 2021

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Aging process is a complicated process that involves deteriorated performance at multiple levels from cellular dysfunction to organ degeneration. For many years research has been focused on how aging changes things within cell. However, new findings suggest that microenvironments, circulating factors or inter-tissue communications could also play important roles in the dynamic progression of aging. These out-of-cell mechanisms pass on the signals from the damaged aging cells to other healthy cells or tissues to promote systematic aging phenotypes. This review discusses the mechanisms of how senescence and their secretome, NAD+ metabolism or circulating factors change microenvironments to regulate systematic aging, as well as the potential therapeutic strategies based on these findings for anti-aging interventions.

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“…Combinations with BH3 mimetics such as venetoclax that target the Bcl-2 family of apoptosis inhibitors offer a potential rational combination in the setting of CDK4/6i resistant ER+ breast cancer. BH3 mimetics are part of a class of drugs known as senolytics which induce apoptosis in a senescent cell population and are of particular interest in treating age-related health issues ( 71 , 72 ). Bcl-2 itself is a transcriptional target of ER and is upregulated in up to 90% of ER+ breast cancers ( 73 ).…”

Section: Potential For Rational Therapeutic Combinations With Mdm2imentioning

confidence: 99%

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

2021

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With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2 via inhibition of MDM2 in the CDK4/6i resistance setting.

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Senolytic targets and new strategies for clearing senescent cells

Cited by 39 publications

References 97 publications

Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development

Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development

Dynamic Aging: Channeled Through Microenvironment

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

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