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

Abstract

BACKGROUND:

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.

• Authors: Xiaohuan Gao, Debabrata Saha, Payal Kapur, Thomas Anthony, Edward H Livingston, Sergio Huerta
• Journal: Journal of surgical oncology (J Surg Oncol) Vol. 100 Issue 2 Pg. 149-58 (Aug 01 2009) ISSN: 1096-9098 [Electronic] United States
• PMID: 19507186 (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
• Survivin
• 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)
• Survivin
• Tumor Suppressor Protein p53 (physiology)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (analysis)