Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin
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Treatment of cells with the anti-cancer drug camptothecin (CPT) induces topoisomerase I (Top1)-mediated DNA damage, which in turn affects cell proliferation and survival. In this report, we demonstrate that treatment of the wild-type HCT116 (wt HCT116) human colon cancer cell line and the isogenic p53(-/-) HCT116 and p21(-/-) HCT116 cell lines with a high concentration (250 nm) of CPT resulted in apoptosis, indicating that apoptosis occurred by a p53- and p21-independent mechanism. In contrast, treatment with a low concentration (20 nm) of CPT induced cell cycle arrest and senescence of the wt HCT116 cells, but apoptosis of the p53(-/-) HCT116 and p21(-/-) HCT116 cells. Further investigations indicated that p53-dependent expression of p21 blocked apoptosis of wt HCT116 cells treated with 20 nm, but not 250 nm CPT. Interestingly, blocking of the apoptotic pathway, by Z-VAD-FMK, in p21(-/-) HCT116 cells following treatment with 20 nm CPT did not permit the cells to develop properties of senescence. These observations demonstrated that p21 was required for senescence development of HCT116 cells following treatment with low concentrations of CPT.
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Alkylating agents, topoisomerase inhibitors, γ-irradiation, microtubule inhibitors and, to a lesser extent, vinca alkaloids have all been identified as senescence inducers in preclinical models.
“Alkylating agents 27,95,96 (for example, cisplatin, cyclophosphamide and temozolomide), topoisomerase inhibitors 27,65,91,95 (such as doxorubicin, etoposide and camptothecin) and γ- irradiation 78 , but also microtubule inhibitors 27,97,98 (for example, paclitaxel) and, to a lesser extent, vinca alkaloids 78 (for example, vincristine), have all been identified as senescence inducers in preclinical”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [95]
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- Authors
- Han, Z., Wei, W., Dunaway, S., Darnowski, J. W., Calabresi, P., Sedivy, J., Hendrickson, E. A., Balan, K. V., Pantazis, P., & Wyche, J. H.
- Affiliations
- Brown University (US)
- Rhode Island Hospital (US)
- University of Minnesota (US)
- Corresponding author
- Han, Zhiyong
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 277
- Issue
- 19
- Pages
- 17154-17160
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2080961798
- Cited by
- 262
- References
- 79
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 10 · 2019: 15 · 2018: 5 · 2017: 7 · 2016: 11 · 2015: 6 · 2014: 8 · 2013: 11 · 2012: 15
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01ai035763-09)
- National Institute on Aging (AG16694)
- National Institute of Allergy and Infectious Diseases (AI 35763)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- p21, apoptosis, cellular senescence, camptothecin, topoisomerase I, DNA damage, p53, colon cancer, HCT116 cells, cell cycle arrest, drug-induced senescence
- MeSH terms
- Antineoplastic Agents, Phytogenic, beta-Galactosidase, Bromodeoxyuridine, Camptothecin, Cell Cycle, Colonic Neoplasms, DNA Damage, Dose-Response Relationship, Drug, Humans, Microscopy, Fluorescence, Models, Biological, Protein Binding, Time Factors, Tumor Cells, Cultured, Blotting, Western, Down-Regulation, Tumor Suppressor Protein p53, Cyclins, Cellular Senescence, Apoptosis, Cyclin-Dependent Kinase Inhibitor p21
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