Cardiac glycosides are broad-spectrum senolytics

Guerrero, Ana Tereza Gomes; Herranz, Nicolás; Sun, Bin; Wagner, Verena; Gallage, Suchira; Guiho, Romain; Wolter, Katharina; Pombo, Joaquim; Irvine, EE; Innes, Andrew; Birch, Jodie; Glegola, Justyna; Manshaei, Saba; Heide, Danijela; Dharmalingam, Gopuraja; Harbig, Jule; Olona, Antoni; Behmoaras, Jacques; Dauch, Daniel; Uren, Anthony G.; Zender, Lars; Vérnia, Santiago; Martínez-Barbera, JP; Heikenwälder, Mathias; Withers, D. I.; Gil, Jesús

doi:10.1038/s42255-019-0122-z

Cited by 253 publications

(245 citation statements)

References 65 publications

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“…Piperlongumine -Radiation-induced senescent astrocytes in vivo -Radiation-induced cognitive dysfunction mouse model [205] -SMARCB1 downregulation-induced senescent A375 melanoma cells -Therapy-induced A549 or H358 lung cancer cells [145] -Radiation-induced, replication exhausted and Ras-induced senescent WI38 fibroblasts [206] Curcumin -Patient-derived senescent intervertebral disc cells [207] -Radiation-induced, oncogene-induced and replication-exhausted senescent WI38 fibroblasts [208] Fisetin -Replication-exhausted senescent Ercc1−/− MEFs -Therapy-induced senescent IMR90 senescent cells -Progeroid Ercc1 −/∆ mice and aged C57BL/6 mouse models -Murine and human-derived senescent adipose tissue [209] -Senescent human umbilical vein endothelial cells [210] Metformin -Murine olfactory ensheathing cells ex vivo [211] Panobinostat -Therapy-induced senescent A549 lung and FaDu head and neck cancer cells [212] 17-DMAG -Oxidative-stress-induce primary Ercc1 −/− -progeroid Ercc1 −/∆ mouse model [213] Torin 1 -Murine senescent hepatocytes ex vivo [214] Epigallocatechin gallate (EGCG) -Senescent 3T3-L1 preadipocytes [215] Bafilomycin A1 -Therapy-induced HCT116 colorectal cancer cells [158] Azithromycin and roxithromycin -Therapy-induced senescent MRC-5 and BJ human fibroblasts [216] Fenofibrate -Senescent T/C28a2 human chondrocytes [217] Cardiac glycosides -Therapy-induced senescent A549 lung cancer cells and SK-MEL-103 melanoma cells in vitro and in vivo [218,219] Several natural and synthetic compounds have been tested for their senescence-eliminating effects in a variety of disease models. The table summarizes the primary current preclinical evidence demonstrating the senolytic agent and the experimental model used.…”

Section: Senolytic Model/cell Line Referencementioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

206

150

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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Section: Senolytic Model/cell Line Referencementioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

206

150

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“…Senolytics include the BCL‐2 family inhibitors Navitoclax (ABT‐263) (Zhu et al, 2016) and ABT‐737 (Yosef et al, 2016); the flavonoid fisetin (Yousefzadeh et al, 2018); combinations of tyrosine kinase inhibitors and flavonoids (e.g. dasatinib and quercetin; Zhu et al, 2015); FOXO4‐p53 interfering peptides (Baar et al, 2017); HSP90 chaperone inhibitors (Fuhrmann‐Stroissnigg et al, 2017); and other compounds such as piperlongumine (Wang et al, 2016) and cardiac glycosides (Guerrero et al, 2019; Triana‐Martínez et al, 2019). Senolytics have emerged as promising agents for treatment of pulmonary fibrosis, atherosclerosis, osteoarthritis, type 1 and 2 diabetes mellitus, and neurocognitive decline.…”

Section: Introductionmentioning

confidence: 99%

Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

et al. 2020

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Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal β-galactosidase (SA-β-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-β-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells).Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclaxinduced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.

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“…To understand if GMD prodrugs could eliminate these pro‐tumourigenic senescent clusters, we used the Hesx1 Cre/+ ;Ctnnb1 lox(ex3)/+ ACP mouse model. We have used this system before to assess the senolytic properties of cardiac glycosides (Guerrero et al, 2019). Tumoural cluster‐containing embryonic pituitaries were cultured ex vivo with vehicle or prodrug A (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

“…Multiple fields within a well were acquired in order to include a minimum of 1,000 cells per sample‐well. HCA of the images was processed using the INCell Investigator 2.7.3 software as described previously (Herranz et al, 2015). Briefly, DAPI served as a nuclear mask hence allowed for the segmentation of cells with a Top‐Hat method.…”

Section: Methodsmentioning

confidence: 99%

“…These studies have led to a collective effort to identify “senolytics,” drugs that selectively kill senescent cells. Several senolytics have been identified including dasatinib and quercetin (Zhu et al, 2015), piperlongumine (Wang et al, 2016), FOXO4‐interfering peptides (Baar et al, 2017), HSP90 inhibitors (Fuhrmann‐Stroissnigg et al, 2017), cardiac glycosides (Guerrero et al, 2019; Triana‐Martinez et al, 2019) or the Bcl2 family inhibitors ABT‐263 (navitoclax) and ABT‐737 (Chen et al, 2015; Yosef et al, 2016; Zhu et al, 2016). Currently, Bcl2 family inhibitors have become the gold standard on senolysis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Galactose‐modified duocarmycin prodrugs as senolytics

et al. 2020

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Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age‐related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence‐associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β‐galactosidase, and this has been exploited as a marker for senescence (senescence‐associated β‐galactosidase activity). Consequently, we hypothesized that galactose‐modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose‐modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β‐galactosidase (GLB1)‐dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole‐body irradiation treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β‐catenin‐positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose‐modified duocarmycin prodrugs to treat senescence‐related pathologies.

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Cardiac glycosides are broad-spectrum senolytics

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Cited by 253 publications

References 65 publications

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

Galactose‐modified duocarmycin prodrugs as senolytics

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