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Updated: Sep 30, 2025
SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies
Sajad Fakhri1, Seyed Zachariah Moradi2, Lindsay K DeLiberto3
1Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
Abstract:
Senescence is a special state of tumor suppression induced by cell cycle arrest. However, releasing senescence-associated secretory phenotypes by senescent cells could provide tumorigenic conditions and epigenetic changes in neighboring cells. The conventional anticancer drugs activate therapy-induced senescence by several mechanisms which include an increase in mitochondrial biogenesis and reactive oxygen species, up-regulation of tumor suppressor proteins (e.g., p53, p21, p38, and p16) and modulation of dysregulated signaling mediators, including senescence-associated β-galactosidase, ataxia-telangiectasia mutated/ATM and Rad3-related, checkpoint kinase1/2, phosphatidylinositol 3-kinases/Akt, Ras/Raf pathway, and extracellular signal-regulated kinase/mitogen-activated protein kinase. On the other hand, conventional anticancer agents induce the secretion of procarcinogenic molecules, including inflammatory mediators, such as nuclear factor-κB, tumor necrosis factor-α, and interleukins, and angiogenic mediators, namely vascular endothelial growth factor, in the tumor microenvironment. This condition urges the need for finding novel alternative therapies, novel senolytics, senescence inducers and combination therapies in the regulation of senescence towards the regulation of multiple tumorigenic conditions. This comprehensive review highlights the therapeutic targets and signaling pathways in the senescence of tumor cells. The critical roles of anticancer drug-induced senescence, senolytics, and associated combined administrations are evaluated in the attenuation of cellular senescence pathways to achieve cancer prevention and efficient treatment. Current challenges/pitfalls, limitations, and future research are also discussed.
Insights
Senescence, a tumor suppression state, can paradoxically promote cancer via secreted factors. Novel senolytics and combination therapies are crucial for effective cancer treatment by regulating senescence pathways.
Area of Science:
- Oncology
- Cellular Biology
- Molecular Medicine
Background:
- Cellular senescence is a state of cell cycle arrest that acts as a tumor suppression mechanism.
- However, senescent cells can secrete factors that promote tumorigenesis and alter neighboring cells epigenetically.
- Conventional anticancer drugs induce senescence but also trigger pro-tumorigenic secretions in the tumor microenvironment.
Purpose of the Study:
- To review therapeutic targets and signaling pathways involved in tumor cell senescence.
- To evaluate the role of anticancer drug-induced senescence, senolytics, and combination therapies in cancer treatment.
- To discuss current challenges, limitations, and future research directions in senescence-based cancer therapies.
Main Methods:
- Comprehensive review of existing literature on cellular senescence in cancer.
- Analysis of mechanisms by which conventional anticancer drugs induce senescence.
- Evaluation of signaling pathways modulated by senescence, including p53, p21, and MAPK pathways.
Main Results:
- Conventional chemotherapy induces senescence via increased reactive oxygen species, tumor suppressor protein upregulation, and modulation of key signaling mediators.
- These therapies also promote secretion of pro-carcinogenic molecules like inflammatory mediators (NF-κB, TNF-α) and angiogenic factors (VEGF).
- The dual role of senescence necessitates exploration of novel senolytics and combination strategies.
Conclusions:
- Targeting senescence pathways offers a promising avenue for cancer prevention and treatment.
- Development of novel senolytics and optimized combination therapies is essential to overcome the pro-tumorigenic effects of senescence.
- Further research is needed to address current challenges and limitations in harnessing senescence for therapeutic benefit.
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