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

Mechanisms of radioresistance in rectal cancer remain unclear.
To determine mechanisms of radioresistance in rectal cancer cells and to assess the role of the nitric oxide donor DETANONOate as a radiosensitizing agent.
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.
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.
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
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: