Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

By Yi Zhu, T. Tchkonia, Heike Fuhrmann-Stroissnigg, Haiming Dai, Y. Ling, Michael B. Stout, T. Pirtskhalava, N. Giorgadze, Kurt O. Johnson, Cory B. Giles and 4 more. Aging Cell, 2016

1,003 citations recorded by the source corpus.

Clearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a043b9b9f72389dcca5366e52da7c7f04c38c557

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Immunology

In Molecular Biology

Citations in the corpus

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies (2021, background): “Since the “inflamm-aging” of endothelial cells contributes to endothelial dysfunction and CVD, therapies such as resveratrol (Du et al., 2019), rapamycin (Sasaki et al., 2020), chlorogenic acid (Hada et al., 2020), and senolytic therapies [B-cell lymphoma 2 inhibitor ABT263 (Zhu et al., 2016), querc”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “It has been shown to be effective in killing senescent preadipocytes, endothelial cells, and mouse embryonic fibroblasts (MEF) in vitro (368).”
Cellular Senescence: A Translational Perspective (2017, methodology): “Using several different approaches in preclinical studies, the combination of D+ Q as well as N were shown to clear senescent cells in vivo (Zhu et al., 2015a; Zhu et al., 2015b; Roos et al., 2016; Schafer et al., 2017; Chang et al., 2016).”
Inflammaging and 'Garb-aging'. (2017, background): “Caloric restriction-mimetic therapies such as metformin, acarbose, rapamycin and senolytic agents (drugs that kill senescent cells) can likely halt inflammation as they activate the disposal of unwanted/damaged cells (and cell components), therefore avoiding the activation of PRR, similarly to what ”
Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease (2019, positive): “For example, based on our report that BCL-xL is an endothelial cell SCAP pathway target in early 2015 [32], we subsequently found that the BCL-2 family inhibitor, Navitoclax (N; also known as ABT-263), and themore specific BCL-xL inhibitors, A1331852 and A1155463, are, like Q, senolytic in the case ”
Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “Navitoclax (ABT263 and ABT737) specifically eliminates various senescent cells via inhibiting BCL-2 family proteins and promoting cell apoptosis.(598,691,692) And Dasatinib, quercetin, and Fisetin eliminate senescent cells via inhibiting PI3K-AKT pathway.”
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study (2019, background): “A1331852, and A1155463, are senolytic, at least with some types of senescent cells [18,57,58].”
Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice (2016, background): “…(Shi et al., 2007), diabetes (Verzola et al., 2008), tobacco exposure (Nyunoya et al., 2006), or atherosclerosis (Wang & Bennett, 2012), and short-term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging-related phenotypes (Zhu et al., 2015a,b).”
Mechanisms and functions of cellular senescence. (2018, neutral): “One of the most widely used senolytics are BCL-2 family inhibitors that target apoptotic resistance of senescent cells (19, 123, 124).”