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

Konjeti R. Sekhar, Vijayakumar N. Sonar, Venkatraj Muthusamy, Soumya Sasi, Andrei Laszlo, Jamil Sawani, Nobuo Horikoshi, Ryuji Higashikubo, Robert G. Bristow, Michael J. Borrelli, Peter A. Crooks, James R. Lepock, Joseph L.Roti Roti, Michael L. Freeman

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)695-701
Number of pages7
JournalCancer research
Volume67
Issue number2
DOIs
StatePublished - Jan 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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