Skip to main content
SpringerLink
Log in

The Importance of p53 Signaling in the Response of Cells to Checkpoint Inhibitors

  • Chapter
  • First Online:
Checkpoint Controls and Targets in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Many anticancer agents induce DNA damage resulting in arrest of cell cycle progression and thereby permit time for repair and recovery. Accordingly, these cell cycle checkpoints limit the efficacy of DNA-damaging agents. Chk1 inhibitors have been developed to prevent arrest and enhance cell killing. This approach would also kill normal cells if it were not for the protective role played by the p53 tumor suppressor. This chapter discusses how p53 can protect cells from DNA damage rather than induce apoptosis, and how activation of p53 in nontumor tissues could enhance the therapeutic index when a patient with a p53 defective tumor is administered a combination of a DNA-damaging agent plus Chk1 inhibitor.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rauth AM (1967) Evidence for dark reactivation of ultraviolet light damaged DNA in mouse L cells. Radiat Res 31:121–138

    Article  CAS  PubMed  Google Scholar 

  2. Lau CC, Pardee AB (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci USA 79:2942–2946

    Article  CAS  PubMed  Google Scholar 

  3. Blasina A, Price BD, Turenne GA, McGowan CH (1999) Caffeine inhibits the checkpoint kinase ATM. Curr Biol 9:1135–1138

    Article  CAS  PubMed  Google Scholar 

  4. Sarkaria JN, Busby EC, Tibbetts RS et al (1999) Inhibition of ATM and ATR kinase by the radiosensitizing agent, caffeine. Cancer Res 59:4375–4382

    CAS  PubMed  Google Scholar 

  5. Bunch RT, Eastman A (1996) Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin Cancer Res 2:791–797

    CAS  PubMed  Google Scholar 

  6. Wang Q, Worland PJ, Clark JL, Carlson BA, Sausville EA (1995) Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Different 6:927–936

    CAS  Google Scholar 

  7. Eastman A, Jennerwein MM, Nagel D (1988) Characterization of bifunctional adducts produced in DNA by trans-diamminedichloroplatinum(II). Chem Biol Interact 67:71–80

    Article  CAS  PubMed  Google Scholar 

  8. Sorenson CM, Eastman A (1988) Mechanism of cis-diamminedichloroplatinum(II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. Cancer Res 48:4484–4488

    CAS  PubMed  Google Scholar 

  9. Sorenson CM, Barry MA, Eastman A (1990) Analysis of events associated with cell cycle arrest at G2 and cell death induced by cisplatin. J Nat Cancer Inst 82:749–754

    Article  CAS  PubMed  Google Scholar 

  10. Demarcq C, Bunch RT, Creswell D, Eastman A (1994) The role of cell cycle progression in cisplatin-induced apoptosis in Chinese hamster ovary cells. Cell Growth Different 5:983–993

    CAS  Google Scholar 

  11. Russell KJ, Wiens LW, Demers GW, Galloway DA, Plon SE, Groudine M (1995) Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res 55:1639–1642

    CAS  PubMed  Google Scholar 

  12. Powell SN, DeFrank JS, Connell P et al (1995) Differential sensitivity of p53(−) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res 55:1643–1648

    CAS  PubMed  Google Scholar 

  13. Fan S, Smith ML, Rivet DJ et al (1995) Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res 55:1649–1654

    CAS  PubMed  Google Scholar 

  14. Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O’Connor PM (1996) UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Nat Cancer Inst 88:956–965

    Article  CAS  PubMed  Google Scholar 

  15. Bucher N, Britten CD (2008) G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Br J Cancer 98:523–528

    Article  CAS  PubMed  Google Scholar 

  16. Sanchez Y, Wong C, Thoma RS et al (1997) Conser-vation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277:1497–1501

    Article  CAS  PubMed  Google Scholar 

  17. Graves PR, Yu L, Schwarz JK et al (2000) The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 275:5600–5605

    Article  CAS  PubMed  Google Scholar 

  18. Busby EC, Leistritz DF, Abraham RT, Karnitz LM, Sarkaria JN (2000) The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res 60:2108–2112

    CAS  PubMed  Google Scholar 

  19. Yu Q, Rose JL, Zhang H, Takemura H, Kohn KW, Pommier Y (2002) UCN-01 inhibits p53 up-regulation and abrogates γ-radiation-induced G2-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res 62:5743–5748

    CAS  PubMed  Google Scholar 

  20. Zhang W-H, Poh A, Fanous AA, Eastman A (2008) DNA damage-induced S phase arrest in human breast cancer depends on CHK1, but G2 arrest can occur independently of Chk1, Chk2 or MAPKAPK2. Cell Cycle 7:1668–1677

    CAS  PubMed  Google Scholar 

  21. Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105

    Article  CAS  PubMed  Google Scholar 

  22. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) p53-Deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11:175–189

    Article  CAS  PubMed  Google Scholar 

  23. Rodriguez-Bravo V, Guaita-Esteruelas S, Salvador N, Bachs O, Agell N (2007) Different S/M checkpoint responses of tumor and non-tumor cell lines to DNA replication inhibition. Cancer Res 67:11648–11656

    Article  CAS  PubMed  Google Scholar 

  24. Zhao B, Bower MJ, McDevitt PJ et al (2002) Structural basis for Chk1 inhibition by UCN-01. J Biol Chem 277:46609–46615

    Article  CAS  PubMed  Google Scholar 

  25. Sato S, Fujita N, Tsuruo T (2002) Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21:1727–1738

    Article  CAS  PubMed  Google Scholar 

  26. King FW, Skeen J, Hay N, Shtivelman E (2004) Inhibition of Chk1 by activated PKB/Akt. Cell Cycle 3:634–637

    Article  CAS  PubMed  Google Scholar 

  27. Puc J, Keniry M, Li HS et al (2005) Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 7:193–204

    Article  CAS  PubMed  Google Scholar 

  28. Bozulic L, Surucu B, Hynx D, Hemmings BA (2008) PKBα/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell 30:203–213

    Article  CAS  PubMed  Google Scholar 

  29. Kohn EA, Ruth ND, Brown MK, Livingstone M, Eastman A (2002) Abrogation of the S phase DNA damage checkpoint results in S phase progression or premature mitosis depending on the concentration of UCN-01 and the kinetics of Cdc25C activation. J Biol Chem 277:26553–26564

    Article  CAS  PubMed  Google Scholar 

  30. Levesque AA, Kohn EA, Bresnick E, Eastman A (2005) Distinct roles for p53 transactivation and repression in preventing UCN-01-mediated abrogation of DNA damage-induced S and G2 cell cycle checkpoints. Oncogene 24:3786–3796

    Article  CAS  PubMed  Google Scholar 

  31. Levesque AA, Fanous AA, Poh A, Eastman A (2008) Defective p53 signaling in p53 wildtype tumors attenuates p21waf1 induction and cyclin B repression rendering them sensitive to Chk1 inhibitors that abrogate S and G2 arrest. Mol Cancer Therap 7:252–262

    Article  CAS  Google Scholar 

  32. Husain A, Yan X-J, Rosales N, Aghajanian C, Schwartz GK, Spriggs DR (1997) UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum(II) independent of p53 status. Clin Cancer Res 3:2089–2097

    CAS  PubMed  Google Scholar 

  33. Hirose Y, Berger MS, Pieper RO (2001) Abrogation of the Chk1-mediated G2 checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Cancer Res 61:5843–5849

    CAS  PubMed  Google Scholar 

  34. Levesque AA, Eastman A (2007) p53-based cancer therapies: is defective p53 the Achilles heel of the tumor? Carcinogenesis 28:13–20

    Article  CAS  PubMed  Google Scholar 

  35. Perez RP, Lewis LD, Beelen AP et al (2006) Modula-tion of cell cycle progression in human tumors: a pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the Chk1 inhibitor UCN-01 (NSC 638850). Clin Cancer Res 12:7079–7085

    Article  CAS  PubMed  Google Scholar 

  36. Giannini G, Ristori E, Cerignoli F et al (2002) Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep 3:248–254

    Article  CAS  PubMed  Google Scholar 

  37. Takemura H, Rao VA, Sordet O et al (2006) Defective Mre11-dependent activation of Chk2 by Ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks. J Biol Chem 281:30814–30823

    Article  CAS  PubMed  Google Scholar 

  38. Shi Z, Azuma A, Sampath D, Li Y-X, Huang P, Plunkett W (2001) S-phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine. Cancer Res 61:1065–1072

    CAS  PubMed  Google Scholar 

  39. Sampath D, Shi Z, Plunkett B (2002) Inhibition of cyclin-dependent kinase 2 by the Chk1-Cdc25A pathway during the S phase checkpoint activated by fludarabine: dysregulation by 7-hydroxystaurosporine. Mol Pharmacol 62:680–688

    Article  CAS  PubMed  Google Scholar 

  40. Ewald B, Sampath D, Plunkett W (2007) H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation. Mol Cancer Therap 6:1239–1248

    Article  CAS  Google Scholar 

  41. Brown EJ, Baltimore D (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev 17:615–628

    Article  CAS  PubMed  Google Scholar 

  42. Xiao Z, Xue J, Sowin TJ, Rosenberg SH, Zhang H (2005) A novel mechanism of checkpoint abrogation conferred by Chk1 downregulation. Oncogene 24:1403–1411

    Article  CAS  PubMed  Google Scholar 

  43. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849

    Article  CAS  PubMed  Google Scholar 

  44. Lowe SW, Bodis S, McClatchey A et al (1994) p53 status and the efficacy of cancer therapy. Science 266:807–810

    Article  CAS  PubMed  Google Scholar 

  45. Strasser A, Harris AW, Jacks T, Cory S (1994) DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79:329–339

    Article  CAS  PubMed  Google Scholar 

  46. Komarova EA, Kondratov RV, Wang K et al (2004) Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23:3265–3271

    Article  CAS  PubMed  Google Scholar 

  47. Fei P, Bernhard EJ, El-Deiry WS (2002) Tissue-specific induction of p53 targets in vivo. Cancer Res 62:7316–7327

    CAS  PubMed  Google Scholar 

  48. Vassilev LT, Vu BT, Graves B et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848

    Article  CAS  PubMed  Google Scholar 

  49. Issaeva N, Bozko P, Enge M et al (2004) Small molecular RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10:1321–1328

    Article  CAS  PubMed  Google Scholar 

  50. Shangary S, Qin D, McEachern D et al (2008) Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA 105:3933–3938

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments:

The research from my laboratory that is reviewed here represents the work of many dedicated post-doctoral fellows, students, and technicians. The main contributors to this research program over the past 15 years were Catherine Demarcq, Todd Bunch, Ethan Kohn, Aime Levesque, Edward Bresnick, Wen-Hui Zhang, Andrew Fanous, and Alissa Poh. The research has been supported by the Norris Cotton Cancer Center and the American Cancer Society, and continues to be supported by the National Cancer Institute (CA117874).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, 03756, USA

    Alan Eastman Ph.D.

Authors
  1. Alan Eastman Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan Eastman Ph.D. .

Editor information

Editors and Affiliations

  1. M.D. Anderson Cancer Center, University of Texas, Holcombe Blvd. 1515, Houston, 77030, U.S.A.

    Zahid H. Siddik

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Eastman, A. (2010). The Importance of p53 Signaling in the Response of Cells to Checkpoint Inhibitors. In: Siddik, Z. (eds) Checkpoint Controls and Targets in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-60761-178-3_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-178-3_12

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-177-6

  • Online ISBN: 978-1-60761-178-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation