Pan-mTOR inhibitors sensitize the senolytic activity of navitoclax via mTORC2 inhibition-mediated apoptotic signaling

Xu, Weitong; Zhao, Tingting; Chen, Honghan; Huang, Ning; Gong, Hui; Zhang, Jian; Yang, Yu; Li, Tiepeng; Zhang, Gongchang; Gong, Chuhui; Yang, Ming; Xiao, Hengyi

doi:10.1016/j.bcp.2022.115045

Cited by 9 publications

(3 citation statements)

References 59 publications

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“…Kohei et al reported that pyrrole-imidazole polyamide conjugated with the mitochondria-delivering moiety triphenylphosphonium with targeted mtDNA mutations has the potential to induce senescence in some tumor cells and also has the potential to induce apoptosis when combined with anti-aging drugs in vivo [359]. Xu et al reported that pan-mTOR inhibitors enhanced the senescence activity of navitoclax, thereby reducing the accumulation of SnCs and alleviating the senescent phenotype in cells and Drosophila, providing new evidence for the advantages of combinations in anti-aging therapy [360]. Taken together, the combination of senolytics and senomorphic strategies offers a promising avenue for developing interventions that target the complex biology of aging.…”

Section: Combination Therapiesmentioning

confidence: 99%

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

2024

Aging dis

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Cellular senescence is characterized by the permanent arrest of cell proliferation and is a response to endogenous and exogenous stress. The continuous accumulation of senescent cells (SnCs) in the body leads to the development of aging and age-related diseases (such as neurodegenerative diseases, cancer, metabolic diseases, cardiovascular diseases, and osteoarthritis). In the face of the growing challenge of aging and age-related diseases, several compounds have received widespread attention for their potential to target SnCs. As a result, senolytics (compounds that selectively eliminate SnCs) and senomorphics (compounds that alter intercellular communication and modulate the behavior of SnCs) have become hot research topics in the field of anti-aging. In addition, strategies such as combination therapies and immune-based approaches have also made significant progress in the field of antiaging therapy. In this article, we discuss the latest research on anti-aging targeting SnCs and gain a deeper understanding of the mechanism of action and impact of different anti-aging strategies on aging and age-related diseases, with the aim of providing more effective references and therapeutic ideas for clinical anti-aging treatment in the face of the ever-grave challenges of aging and age-related diseases.

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Section: Combination Therapiesmentioning

confidence: 99%

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

2024

Aging dis

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“…This strategy promoted selective amelioration of senescent cell burden and downregulation of pro-inflammatory cytokines and matrix proteases from degenerative mouse intervertebral disc leading to retardation of progression of intervertebral disc degeneration, and even restructuring of the intervertebral disc structure (Lim et al, 2022). Further, a drug combinatorial strategy involving the simultaneous administration of navitoclax and pan-mTOR inhibitors such as PP242 and AZD8055 was shown to decrease the requeired dosage or timespan of navitoclax needed for reaching IC50 and LT50 in senescent cells while extending the lifespan of premature-aged Drosophila and delaying the onset of aging-related phenotype (Xu et al, 2022).…”

Section: Navitoclax (Abt-263)mentioning

confidence: 99%

Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies

Lucas

Cavadas

Aveleira

2023

Pharmacological Reviews

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An increase in life expectancy in developed countries has led to an insurgency of chronic agingrelated diseases. In the last few decades, several studies provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype (SASP) resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers. Also, strategies to prevent the pathological effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies and some are already in early stages of clinical translation.The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiological functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection.We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies. Significance StatementThis manuscript is an extensive review of what is currently known about the complex process of cellular senescence exploring its most defining features. The main body of the discussion focus on how the multi-feature fluctuation of the senescence phenotype and the physiological role of cellular senescence have both caused a limitation in the search for truly reliable senescence biomarkers and the progression in the development of senotherapies.

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“…Azithromycin, a macrolide antibiotic, effectively eliminated 44% of senescent myofibroblasts at non-cytotoxic doses for control cells, acting as a senolytic drug by a mechanism related to autophagic and metabolic changes [ 25 ]. The mTOR inhibitor rapamycin has senolytic activity by itself, and it is also able to sensitize senolytic cell death induced by navitoclax, suggesting that simultaneous inhibition of mTORC and Bcl-2 could be a new idea for senolytic drug combinations [ 26 , 27 ]. Aspirin, a cyclooxygenase inhibitor mainly used as an antiplatelet drug, reduces cell viability and decreases the levels of Bcl-xL protein in senescent fibroblast [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line

de Godoy,

Macedo,

Gambero

2024

Pharmaceuticals

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Therapeutically targeting senescent cells seems to be an interesting perspective in treating chronic lung diseases, which are often associated with human aging. The combination of the drug dasatinib and the polyphenol quercetin is used in clinical trials as a senolytic, and the first results point to the relief of physical dysfunction in patients with idiopathic pulmonary fibrosis. In this work, we tested new combinations of drugs and polyphenols, looking for senolytic activity using human lung fibroblasts (MRC-5 cell line) with induced senescence. We researched drugs, such as azithromycin, rapamycin, metformin, FK-506, aspirin, and dasatinib combined with nine natural polyphenols, namely caffeic acid, chlorogenic acid, ellagic acid, ferulic acid, gallic acid, epicatechin, hesperidin, quercetin, and resveratrol. We found new effective senolytic combinations with dasatinib and ellagic acid and dasatinib and resveratrol. Both drug combinations increased apoptosis, reduced BCL-2 expression, and increased caspase activity in senescent MRC-5 cells. Ellagic acid senolytic activity was more potent than quercetin, and resveratrol counteracted inflammatory cytokine release during senolysis in vitro. In conclusion, dasatinib and ellagic acid and dasatinib and resveratrol present in vitro senolytic potential like that observed for the combination in clinical trials of dasatinib and quercetin, and maybe they could be future alternatives in the senotherapeutic field.

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Pan-mTOR inhibitors sensitize the senolytic activity of navitoclax via mTORC2 inhibition-mediated apoptotic signaling

Cited by 9 publications

References 59 publications

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies

Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line

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