Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis

Admasu, Tesfahun Dessale; Kim, Kristie; Rae, Michael J.; Avelar, Roberto A.; Gonciarz, Ryan L.; Rebbaa, Abdelhadi; Magalhães, João Pedro de; Renslo, Adam R.; Stolzing, Alexandra; Sharma, Amit

doi:10.1016/j.celrep.2023.112058

Cited by 18 publications

(14 citation statements)

References 82 publications

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“…In contrast, in primary endothelial cells induced to undergo TIS and in paracrine senescent endothelial cells, FPN1 protein levels are reduced when compared to non-senescent cells. The role of FPN1 in this cell system has not been fully analyzed, but both primary and paracrine senescent endothelial cells accumulate high levels of ferrous iron; therefore, a reduction in iron efflux via the downregulation of FPN1 might represent a plausible mechanism for this accumulation [69]. As previously described, FPN1 downregulation has been observed in multiple cancer types in which it provides a mechanism for the retention of intracellular labile iron.…”

Section: Ferroportin (Fpn1)mentioning

confidence: 91%

“…Admasu and colleagues have analyzed both primary endothelial cells induced to undergo TIS with doxorubicin and DPP4-positive paracrine senescent endothelial cells. Both TIS and paracrine senescent endothelial cells accumulate intracellular ferrous iron Fe 2+ , but the iron importer TfR1 is found to be downregulated, suggesting that in this cell system, increased iron uptake is not responsible for the elevated intracellular iron levels [69]. The downregulation of TfR1 has also been described in senescent cancer cells.…”

Section: Transferrin Receptor 1 and 2 (Tfr1 Tfr2)mentioning

confidence: 95%

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Iron Metabolism in Cancer and Senescence: A Cellular Perspective

Crescenzi

Leonardi

Pacifico

2023

Biology

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Iron participates in a number of biological processes and plays a crucial role in cellular homeostasis. Alterations in iron metabolism are considered hallmarks of cancer and drivers of aggressive behaviors, such as uncontrolled proliferation, resistance to apoptosis, enhanced metastatic ability, increased cell plasticity and stemness. Furthermore, a dysregulated iron metabolism has been associated with the development of an adverse tumor microenvironment. Alterations in iron metabolism have been described in cellular senescence and in aging. For instance, iron has been shown to accumulate in aged tissues and in age-related diseases. Furthermore, in vitro studies demonstrate increases in iron content in both replicative and stress-induced senescent cells. However, the role, the mechanisms of regulation and dysregulation and the effects of iron metabolism on senescence remain significantly less characterized. In this review, we first provide an overview of iron metabolism and iron regulatory proteins. Then, we summarize alterations in iron homeostasis in cancer and senescence from a cellular point of view.

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Section: Ferroportin (Fpn1)mentioning

confidence: 91%

Section: Transferrin Receptor 1 and 2 (Tfr1 Tfr2)mentioning

confidence: 95%

Iron Metabolism in Cancer and Senescence: A Cellular Perspective

Crescenzi

Leonardi

Pacifico

2023

Biology

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“…The vast majority of literature pertaining to iron and cellular senescence focuses on the distinct accumulation of iron and iron dyshomeostasis in senescent cells [ 208 , 209 , 210 ]. As such, many studies have begun targeting these iron features for senolytic drugs, particularly inducing ferroptosis [ 211 , 212 , 213 , 214 ]. For more detailed reviews on the roles of iron dyshomeostasis and accumulation in senescent cells, see reviews [ 210 , 215 , 216 , 217 ].…”

Section: Heavy Metals Induce Cellular Senescencementioning

confidence: 99%

Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence

Vielee

Wise

2023

Brain Sciences

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Advancements in modern medicine have improved the quality of life across the globe and increased the average lifespan of our population by multiple decades. Current estimates predict by 2030, 12% of the global population will reach a geriatric age and live another 3–4 decades. This swelling geriatric population will place critical stress on healthcare infrastructures due to accompanying increases in age-related diseases and comorbidities. While much research focused on long-lived individuals seeks to answer questions regarding how to age healthier, there is a deficit in research investigating what aspects of our lives accelerate or exacerbate aging. In particular, heavy metals are recognized as a significant threat to human health with links to a plethora of age-related diseases, and have widespread human exposures from occupational, medical, or environmental settings. We believe heavy metals ought to be classified as a class of gerontogens (i.e., chemicals that accelerate biological aging in cells and tissues). Gerontogens may be best studied through their effects on the “Hallmarks of Aging”, nine physiological hallmarks demonstrated to occur in aged cells, tissues, and bodies. Evidence suggests that cellular senescence—a permanent growth arrest in cells—is one of the most pertinent hallmarks of aging and is a useful indicator of aging in tissues. Here, we discuss the roles of heavy metals in brain aging. We briefly discuss brain aging in general, then expand upon observations for heavy metals contributing to age-related neurodegenerative disorders. We particularly emphasize the roles and observations of cellular senescence in neurodegenerative diseases. Finally, we discuss the observations for heavy metals inducing cellular senescence. The glaring lack of knowledge about gerontogens and gerontogenic mechanisms necessitates greater research in the field, especially in the context of the global aging crisis.

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“…Senescent cells undergo metabolic reprogramming and multiple phenotypic alterations, increasing cytosolic polyunsaturated fatty acids (PUFAs) and ferrous ions levels . PUFAs and Fe 2+ are essential for lipid peroxidation; therefore, senescent cells show increased susceptibility to ferroptosis. , Cellular senescence can be triggered by various drugs, among which cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors (e.g., palbociclib) are potent pro-senescent agents, resulting in cell cycle arrest at G 0 /G 1 phase. , Moreover, palbociclib can increase the activities of two rate-limiting enzymes during glycolysis, phosphofructokinase 1 (PFK1) and pyruvate kinase M2 (PKM2), which causes the depletion of GSH and NADPH, and ferroptosis sensitization …”

Section: Introductionmentioning

confidence: 99%

Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion

Fan,

Du,

et al. 2024

ACS Nano

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Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G 0 /G 1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.

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Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis

Cited by 18 publications

References 82 publications

Iron Metabolism in Cancer and Senescence: A Cellular Perspective

Iron Metabolism in Cancer and Senescence: A Cellular Perspective

Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence

Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion

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