Display options
Cite
Asuncion Valenzuela MM, Castro I, Gonda A, et al. Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase. Onco Targets Ther. 2015;8:495-507doi: 10.2147/OTT.S79647.
Asuncion Valenzuela, M. M., Castro, I., Gonda, A., Diaz Osterman, C. J., Jutzy, J. M., Aspe, J. R., Khan, S., Neidigh, J. W., & Wall, N. R. (2015). Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase. OncoTargets and therapy, 8495-507. https://doi.org/10.2147/OTT.S79647
Asuncion Valenzuela, Malyn M, et al. "Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase." OncoTargets and therapy vol. 8 (2015): 495-507. doi: https://doi.org/10.2147/OTT.S79647
Asuncion Valenzuela MM, Castro I, Gonda A, Diaz Osterman CJ, Jutzy JM, Aspe JR, Khan S, Neidigh JW, Wall NR. Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase. Onco Targets Ther. 2015 Feb 26;8:495-507. doi: 10.2147/OTT.S79647. eCollection 2015. PMID: 25767396; PMCID: PMC4354452.
Copy Download .nbib Format: NLM
Share it on

Onco Targets Ther. 2015 Feb 26;8:495-507. doi: 10.2147/OTT.S79647. eCollection 2015.

Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase.

OncoTargets and therapy

Malyn M Asuncion Valenzuela, Imilce Castro, Amber Gonda, Carlos J Diaz Osterman, Jessica M Jutzy, Jonathan R Aspe, Salma Khan, Jonathan W Neidigh, Nathan R Wall

Affiliations

  1. Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.

PMID: 25767396 PMCID: PMC4354452 DOI: 10.2147/OTT.S79647

Abstract

New agent development, mechanistic understanding, and combinatorial partnerships with known and novel modalities continue to be important in the study of pancreatic cancer and its improved treatment. In this study, known antimetabolite drugs such as gemcitabine (ribonucleotide reductase inhibitor) and 5-fluorouracil (thymidylate synthase inhibitor) were compared with novel members of these two drug families in the treatment of a chemoresistant pancreatic cancer cell line PANC-1. Cellular survival data, along with protein and messenger ribonucleic acid expression for survivin, XIAP, cIAP1, and cIAP2, were compared from both the cell cytoplasm and from exosomes after single modality treatment. While all antimetabolite drugs killed PANC-1 cells in a time- and dose-dependent manner, neither family significantly altered the cytosolic protein level of the four inhibitors of apoptosis (IAPs) investigated. Survivin, XIAP, cIAP1, and cIAP2 were found localized to exosomes where no significant difference in expression was recorded. This inability for significant and long-lasting expression may be a reason why pancreatic cancer lacks responsiveness to these and other cancer-killing agents. Continued investigation is required to determine the responsibilities of these IAPs in their role in chemoresistance in pancreatic adenocarcinoma.

Keywords: 5-fluorodeoxyuridine; 5-fluorouracil; IAPs; antimetabolites; cladribine; exosomes; gemcitabine; hydroxyurea; pancreatic cancer

References

  1. Anticancer Res. 1998 Sep-Oct;18(5A):3433-7 - PubMed
  2. Apoptosis. 2011 Jan;16(1):1-12 - PubMed
  3. Int J Cancer. 2007 Jun 1;120(11):2344-52 - PubMed
  4. EMBO J. 1997 Dec 1;16(23 ):6914-25 - PubMed
  5. Nat Med. 1998 May;4(5):594-600 - PubMed
  6. J Cell Physiol. 2003 Oct;197(1):8-29 - PubMed
  7. Nat Rev Cancer. 2008 Jan;8(1):61-70 - PubMed
  8. Scand J Gastroenterol. 2009;44(7):782-6 - PubMed
  9. N Engl J Med. 1992 Feb 13;326(7):455-65 - PubMed
  10. Clin Exp Pharmacol Physiol. 1998 Nov;25(11):887-95 - PubMed
  11. Nat Med. 2001 Mar;7(3):297-303 - PubMed
  12. Cancer Res. 2007 Apr 1;67(7):2912-5 - PubMed
  13. J Biol Chem. 2003 Mar 21;278(12 ):10055-60 - PubMed
  14. Clin Cancer Res. 2008 Aug 15;14(16):5000-5 - PubMed
  15. J Biochem. 2006 Jul;140(1):13-21 - PubMed
  16. J Biol Chem. 2006 Feb 10;281(6):3254-60 - PubMed
  17. Clin Cancer Res. 2004 May 1;10(9):2936-43 - PubMed
  18. Lancet. 2002 Jul 27;360(9329):295-305 - PubMed
  19. Cancer Sci. 2009 May;100(5):903-13 - PubMed
  20. Br J Surg. 2004 May;91(5):586-94 - PubMed
  21. CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30 - PubMed
  22. Cell Death Differ. 2008 Jan;15(1):80-8 - PubMed
  23. Genes Dev. 1999 Feb 1;13(3):239-52 - PubMed
  24. Chemotherapy (Los Angel). 2014 Dec;3(3):null - PubMed
  25. ISRN Oncol. 2012;2012:928120 - PubMed
  26. Proteomics. 2004 Dec;4(12):4019-31 - PubMed
  27. Cancer. 1995 Nov 1;76(9):1671-7 - PubMed
  28. Ann Oncol. 2006 May;17 Suppl 5:v7-12 - PubMed
  29. Lab Invest. 2010 Nov;90(11):1549-57 - PubMed
  30. Nat Struct Biol. 2000 Jul;7(7):602-8 - PubMed
  31. J Clin Oncol. 2009 Aug 10;27(23):3778-85 - PubMed
  32. Thromb Res. 2010 Apr;125 Suppl 1:S49-51 - PubMed
  33. Pancreas. 2009 Oct;38(7):782-90 - PubMed
  34. Anticancer Res. 2012 May;32(5):1681-8 - PubMed
  35. Onco Targets Ther. 2010 Sep 07;3:111-27 - PubMed
  36. Ann Oncol. 2003;14 Suppl 5:v128-49 - PubMed
  37. Cancer Lett. 2012 Jul 28;320(2):138-49 - PubMed
  38. Br J Cancer. 2009 Apr 7;100(7):1073-86 - PubMed
  39. Gut. 2005 Mar;54(3):385-7 - PubMed
  40. J Clin Oncol. 2005 May 20;23(15):3509-16 - PubMed
  41. Anticancer Res. 1999 Jul-Aug;19(4C):3439-45 - PubMed
  42. Oncology (Williston Park). 2002 Jun;16(6):725-34; discussion 734, 736-8, 740, 743 - PubMed
  43. Nat Rev Drug Discov. 2012 Feb 01;11(2):109-24 - PubMed
  44. Anticancer Res. 2006 Sep-Oct;26(5A):3265-73 - PubMed
  45. Nat Cell Biol. 1999 Dec;1(8):461-6 - PubMed
  46. Mol Cell. 2008 Apr 25;30(2):123-35 - PubMed
  47. Nature. 1997 Jul 17;388(6639):300-4 - PubMed
  48. Immunol Res. 2006;36(1-3):247-54 - PubMed
  49. J Clin Oncol. 2002 Mar 15;20(6):1512-8 - PubMed
  50. Biochem J. 2010 Sep 1;430(2):199-205 - PubMed
  51. Nat Rev Cancer. 2003 May;3(5):330-8 - PubMed
  52. Trends Cell Biol. 1999 Aug;9(8):323-8 - PubMed
  53. Expert Opin Ther Targets. 2009 Nov;13(11):1333-45 - PubMed
  54. Nat Rev Cancer. 2003 Jan;3(1):46-54 - PubMed
  55. Cancer Lett. 2014 Mar 1;344(1):101-9 - PubMed
  56. Am J Pathol. 2004 May;164(5):1807-15 - PubMed

Publication Types

Grant support