Identification of GL-V9 as a novel senolytic agent against senescent breast cancer cells

Yang, Dawei; Tian, Xiaoyu; Ye, Yuchen; Liang, Yin; Zhao, Jie; Wu, Tao; Lu, Na

doi:10.1016/j.lfs.2021.119196

Cited by 26 publications

(23 citation statements)

References 33 publications

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“…GL-V9, a synthetic flavonoid analogue of wogonin, has been demonstrated to have pro-apoptotic, antiinvasive, anti-metastatic, anti-tumour and autophagic effects in various cancer cells [84][85][86][87]. Recently, GL-V9 was shown to be a potential senolytic that preferentially killed senescent breast cancer cells and replication-induced senescent MEFs in a ROSdependent manner [88]. In senescent MDA-MB-231 cells, GL-V9 at 10 lM was able to alkalize the lysosome and elevate ROS levels, aggravating mitophagy deficiency, to induce apoptosis.…”

Section: Gl-v9mentioning

confidence: 99%

Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

et al. 2022

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The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene‐induced stress. Many senescent cells (SnCs) develop a senescent‐associated secretory phenotype (SASP) comprising pro‐inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up‐regulate senescent cell anti‐apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age‐related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre‐clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.

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Section: Gl-v9mentioning

confidence: 99%

Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

et al. 2022

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“…In order to improve the bioavailability and efficacy of the poorly absorbed wogonin, analogs such as GL-V9 with a broad spectrum of action have been formulated through structural modifications. In a recent report, GL-V9 showed potential senolytic effects against senescent breast cancer cells mediated through ROS-dependent apoptotic mechanism [ 87 ]. Thus, further research on the anti-senescence effects of wogonin and GL-V9 in other senescence-associated diseases is required.…”

Section: Polyphenolic Flavonoidsmentioning

confidence: 99%

Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection

2022

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Cellular senescence, a hallmark of ageing, contributes to tissue or organ dysfunction and the pathophysiology of diverse age-related diseases (ARD) by various mechanisms. Targeting it by selective elimination of senescent cells (SCs) or blocking senescence-associated secretory phenotypes (SASP) with natural or synthetic compounds has been suggested to improve lifespan. Dietary phytochemicals possess a broad spectrum of biochemical and pharmacological effects that are beneficial to human health. Flavonoids, which are widely consumed in fruits and vegetables worldwide, are emerging as potential therapeutic agents to mitigate senescence. Naringenin, hesperetin, hesperidin, quercetin, fisetin, kaempferol, rutin, apigenin, luteolin, nobiletin, tangeretin, genistein, wogonin, epigallocatechin gallate (EGCG), theaflavin-3-gallate (TF2A), and procyanidin C1 possess potent antisenescence effects. A single biochemical process may not explain their pleiotropic pharmacological impact. Flavonoids directly modulate underlying cellular senescence processes or interact with molecular targets that regulate ageing-related pathways. This review discusses the potential use of flavonoids to mitigate senescence and consequently delay the onset of ageing-related diseases. We also highlight the underlying mechanisms of action of flavonoids as potential senotherapeutics and reflect on future perspectives and possible strategies to optimize and increase the translatability from bench to bedside in senotherapy.

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“…GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy)-4-H-chromen-4-one), a new synthetic flavonoid derived from wogonin, can efficiently induce apoptosis of senescent MDA-MB-231 and MCF cells in vitro through a ROS-dependent mechanism. More importantly, the inhibitory effect of GL-V9 on senescent cancer cells is similar to that of the classic anti-senescence combination, quercetin + dasatinib, and better than that of quercetin alone [ 83 ]. Hence, GL-V9 is a promising antisenescence agent.…”

Section: Treatment Strategies Based On the Aging Microenvironmentmentioning

confidence: 99%

Recent Advances in the Aging Microenvironment of Breast Cancer

Jiang

Shen

Shang

et al. 2022

Cancers

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Aging is one of the risk factors for advanced breast cancer. With the increasing trend toward population aging, it is important to study the effects of aging on breast cancer in depth. Cellular senescence and changes in the aging microenvironment in vivo are the basis for body aging and death. In this review, we focus on the influence of the aging microenvironment on breast cancer. Increased breast extracellular matrix stiffness in the aging breast extracellular matrix can promote the invasion of breast cancer cells. The role of senescence-associated secretory phenotypes (SASPs) such as interleukin-6 (IL-6), IL-8, and matrix metalloproteases (MMPs), in breast cancer cell proliferation, invasion, and metastasis is worthy of exploration. Furthermore, the impact of senescent fibroblasts, adipocytes, and endothelial cells on the mammary matrix is discussed in detail. We also list potential targets for senotherapeutics and senescence-inducing agents in the aging microenvironment of breast cancer. In conclusion, this review offers an overview of the influence of the aging microenvironment on breast cancer initiation and progression, with the aim of providing some directions for future research on the aging microenvironment in breast cancer.

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Identification of GL-V9 as a novel senolytic agent against senescent breast cancer cells

Cited by 26 publications

References 33 publications

Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection

Recent Advances in the Aging Microenvironment of Breast Cancer

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