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Radiosensitization of HT-29 cells and xenografts by the nitric oxide donor DETANONOate.

AbstractBACKGROUND:
Mechanisms of radioresistance in rectal cancer remain unclear.
OBJECTIVES:
To determine mechanisms of radioresistance in rectal cancer cells and to assess the role of the nitric oxide donor DETANONOate as a radiosensitizing agent.
METHODS:
Survival was determined by clonogenic assays, apoptosis by PARP-1 cleavage, and phenotypic differences by Western blot analysis. SCID mice bearing HT-29 xenografts were treated with ionizing radiation (IR) [2.0 Gy x 5], DETANONOate [0.4 mg/kg i.p.], or combination treatment.
RESULTS:
Colorectal cancer HT-29-p53-null cells were resistant and HCT-116-p53 wild-type cells sensitive to IR, which correlated with cleaved PARP-1. Increased levels of p21 occurred in HCT-116 cells, while Bcl-2 and survivin were elevated in HT-29 cells. Radiosensitization was achieved with a substantial elevation of cleaved PARP-1 in DETANONOate-HT-29-treated versus control cells, which was accompanied by elevation of p21, p27, and BAX, and a concomitant decrease in Bcl-2. SCID mice bearing HT-29 xenografts demonstrated a 37.6%, 51.1%, and 70.1% inhibition in tumor growth in mice receiving IR, DETANONOate, and combination treatment versus control, respectively.
CONCLUSIONS:
Radioresistant HT-29 cells are p53-null and have substantially decreased levels of p21. DETANONOate radiosensitized HT-29 cells in vitro and in vivo by an additive effect in apoptosis.
AuthorsXiaohuan Gao, Debabrata Saha, Payal Kapur, Thomas Anthony, Edward H Livingston, Sergio Huerta
JournalJournal of surgical oncology (J Surg Oncol) Vol. 100 Issue 2 Pg. 149-58 (Aug 1 2009) ISSN: 1096-9098 [Electronic] United States
PMID19507186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • 2,2'-(hydroxynitrosohydrazono)bis-ethanamine
Topics
  • Animals
  • Dose-Response Relationship, Drug
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mice, SCID
  • Microtubule-Associated Proteins (physiology)
  • Nitric Oxide Donors (pharmacology)
  • Nitroso Compounds (pharmacology)
  • Radiation-Sensitizing Agents (pharmacology)
  • Tumor Suppressor Protein p53 (physiology)
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein (analysis)

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