Therapy-induced Senescence in Cancer

Overview

Journal J Natl Cancer Inst

Publisher Oxford University Press

Specialty Oncology

Date 2010 Sep 23

PMID 20858887

Citations 418

Authors

Jonathan A Ewald

Joshua A Desotelle

George Wilding

David F Jarrard

Affiliations

Soon will be listed here.

Abstract

Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer.

Citing Articles

Antioxidant Senotherapy by Natural Compounds: A Beneficial Partner in Cancer Treatment.

Aleksandrova Y, Neganova M Antioxidants (Basel). 2025; 14(2).

PMID: 40002385 PMC: 11851806. DOI: 10.3390/antiox14020199.

Pharmacological CDK4/6 inhibition promotes vulnerability to lysosomotropic agents in breast cancer.

Nehme J, Maassen S, Bravaccini S, Zanoni M, Gianni C, De Giorgi U EMBO J. 2025; .

PMID: 39930269 DOI: 10.1038/s44318-025-00371-x.

Petroleum ether extract of induces senescence and inhibits invasion in breast cancer MDA-MB-231 cells.

Long T, Phuong L, Van Nguyen Dang L, Ngoc T, Thao D, Trinh N 3 Biotech. 2025; 15(2):45.

PMID: 39834568 PMC: 11741969. DOI: 10.1007/s13205-025-04214-8.

The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities.

Wang Z, Chen C, Ai J, Gao Y, Wang L, Xia S MedComm (2020). 2025; 6(1):e70048.

PMID: 39811803 PMC: 11731108. DOI: 10.1002/mco2.70048.

The Hippo Signaling Pathway Manipulates Cellular Senescence.

Miyajima C, Nagasaka M, Aoki H, Toriuchi K, Yamanaka S, Hashiguchi S Cells. 2025; 14(1.

PMID: 39791714 PMC: 11719916. DOI: 10.3390/cells14010013.

References

dAdda di Fagagna F . Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008; 8(7):512-22. DOI: 10.1038/nrc2440. View

Bukowski R, Fleming T, Macdonald J, Oishi N, Taylor S, Baker L . Evaluation of combination chemotherapy and phase II agents in pancreatic adenocarcinoma. A Southwest Oncology Group study. Cancer. 1993; 71(2):322-5. DOI: 10.1002/1097-0142(19930115)71:2<322::aid-cncr2820710209>3.0.co;2-g. View

Gewirtz D, Holt S, Elmore L . Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem Pharmacol. 2008; 76(8):947-57. DOI: 10.1016/j.bcp.2008.06.024. View

Xu H, Zhou Y, Ji W, Perng G, Kruzelock R, Kong C . Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition. Oncogene. 1997; 15(21):2589-96. DOI: 10.1038/sj.onc.1201446. View

DeSimone D . Replicative potentials of various fusion products between WI-38 and SV40 transformed WI-38 cells and their components. Somatic Cell Genet. 1980; 6(6):689-98. DOI: 10.1007/BF01538968. View

Roberson R, Kussick S, Vallieres E, Chen S, Wu D . Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 2005; 65(7):2795-803. DOI: 10.1158/0008-5472.CAN-04-1270. View

Te Poele R, Okorokov A, Jardine L, Cummings J, Joel S . DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002; 62(6):1876-83. View

Jung M, Yun J, Chae H, Kim J, Kim S, Choi T . p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor. Oncogene. 2001; 20(41):5818-25. DOI: 10.1038/sj.onc.1204748. View

Zhang H, Pan K, Cohen S . Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc Natl Acad Sci U S A. 2003; 100(6):3251-6. PMC: 152278. DOI: 10.1073/pnas.2627983100. View

10.

Smith J . Expression of SV40 T antigen in finite life-span hybrids of normal and SV40-transformed fibroblasts. Somatic Cell Genet. 1981; 7(4):411-21. DOI: 10.1007/BF01542986. View

11.

Heiss E, Schilder Y, Dirsch V . Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. J Biol Chem. 2007; 282(37):26759-26766. DOI: 10.1074/jbc.M703229200. View

12.

Schwarze S, Shi Y, Fu V, Watson P, Jarrard D . Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene. 2002; 20(57):8184-92. DOI: 10.1038/sj.onc.1205049. View

13.

Michaloglou C, Vredeveld L, Soengas M, Denoyelle C, Kuilman T, van der Horst C . BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436(7051):720-4. DOI: 10.1038/nature03890. View

14.

Zhang R, Chen W, Adams P . Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol. 2007; 27(6):2343-58. PMC: 1820509. DOI: 10.1128/MCB.02019-06. View

15.

Hampel B, Malisan F, Niederegger H, Testi R, Jansen-Durr P . Differential regulation of apoptotic cell death in senescent human cells. Exp Gerontol. 2004; 39(11-12):1713-21. DOI: 10.1016/j.exger.2004.05.010. View

16.

Sugrue M, Shin D, Lee S, Aaronson S . Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc Natl Acad Sci U S A. 1997; 94(18):9648-53. PMC: 23243. DOI: 10.1073/pnas.94.18.9648. View

17.

Zhang R, Adams P . Heterochromatin and its relationship to cell senescence and cancer therapy. Cell Cycle. 2007; 6(7):784-9. DOI: 10.4161/cc.6.7.4079. View

18.

Campisi J . Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120(4):513-22. DOI: 10.1016/j.cell.2005.02.003. View

19.

Bunn C, Tarrant G . Limited lifespan in somatic cell hybrids and cybrids. Exp Cell Res. 1980; 127(2):385-96. DOI: 10.1016/0014-4827(80)90443-7. View

20.

Roninson I . Tumor cell senescence in cancer treatment. Cancer Res. 2003; 63(11):2705-15. View