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The Achilles' heel of cancer survivors: fundamentals of accelerated cellular senescence.

ABSTRACT: Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment-induced early aging accounts for significant morbidity, mortality, and health expenditures among cancer survivors. One major mechanism driving this accelerated aging is cellular senescence; cancer treatments induce cellular senescence in tumor cells and in normal, nontumor tissue, thereby helping mediate the onset of several chronic diseases. Studies on clinical monitoring and therapeutic targeting of cellular senescence have made considerable progress in recent years. Large-scale clinical trials are currently evaluating senotherapeutic drugs, which inhibit or eliminate senescent cells to ameliorate cancer treatment-related aging. In this article, we survey the recent literature on phenotypes and mechanisms of aging in cancer survivors and provide an up-to-date review of the major preclinical and translational evidence on cellular senescence as a mechanism of accelerated aging in cancer survivors, as well as insight into the potential of senotherapeutic drugs. However, only with time will the clinical effect of senotherapies on cancer survivors be visible.

SUBMITTER: Shafqat S

PROVIDER: S-EPMC9246373 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions.

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Incomplete ablation of thyroid cancer: Achilles' Heel?

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| S-EPMC3619664 | biostudies-literature

Targeting ferroptosis, the achilles’ heel of breast cancer: A review

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Senescent cells: A new Achilles' heel to exploit for cancer medicine?

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| S-EPMC6351840 | biostudies-literature

Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.

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| S-EPMC10952006 | biostudies-literature

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| S-EPMC7552172 | biostudies-literature

Calibration: the Achilles heel of predictive analytics.

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Project description:Mycobacterial pathogens adapt to environmental stresses such as nutrient deprivation by entering a non-replicative antibiotic-tolerant state of persistence. Using a biochemically-validated data-driven approach, we identified an adaptive metabolic network underlying the mycobacterial response to starvation in M. tuberculosis, M. bovis BCG and M. smegmatis. All three species show a strong Mg+2-dependence for surviving complete nutrient deprivation, accompanied by a broad phenotypic antibiotic resistance. Multivariate analysis of RNA-seq, metabolic phenotyping and biochemical data revealed substantial metabolic remodelling involving a shift to triacylglycerol utilization with adaptation to the consequent ketoacidosis by upregulation of cytochrome P450s. Paradoxically, the ketosis-driven P450 upregulation generated substantial levels of reactive oxygen species (ROS) yet conferred hypersensitivity to killing by hydrogen peroxide-induced inactivation of the P450s that reduced ROS levels. This emergent property of starvation-induced mycobacterial persistence represents a potentially exploitable vulnerability.

2016-08-25 | GSE66883 | GEO

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