Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway.

Sekhar KR, Sonar VN, Muthusamy V, Sasi S, Laszlo A, Sawani J, Horikoshi N, Higashikubo R, Bristow RG, Borrelli MJ, Crooks PA, Lepock JR, Roti Roti JL, Freeman ML
Cancer Res. 2007 67 (2): 695-701

PMID: 17234780 · DOI:10.1158/0008-5472.CAN-06-3212

Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing novel small molecules that could function as thermal radiosensitizers. (Z)-(+/-)-2-(1-Benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol was identified as a compound that could lower the threshold for Hsf1 activation and thermal sensitivity. Enhanced thermal sensitivity was associated with significant thermal radiosensitization. We established the structural requirements for activity: the presence of an N-benzenesulfonylindole or N-benzylindole moiety linked at the indolic 3-position to a 2-(1-azabicyclo[2.2.2]octan-3-ol) or 2-(1-azabicyclo[2.2.2]octan-3-one) moiety. These small molecules functioned by exploiting the underlying biophysical events responsible for thermal sensitization. Thermal radiosensitization was characterized biochemically and found to include loss of mitochondrial membrane potential, followed by mitotic catastrophe. These studies identified a novel series of small molecules that represent a promising tool for the treatment of recurrent tumors by ionizing radiation.

MeSH Terms (12)

Colonic Neoplasms DNA-Binding Proteins HCT116 Cells Heat Shock Transcription Factors Humans Hyperthermia, Induced Indoles Mitosis Protein Conformation Radiation-Sensitizing Agents Structure-Activity Relationship Transcription Factors

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