title: Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway.
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.
authors.affiliation: Department of Radiation Oncology/Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA, and Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Konjeti R
authors.initials: KR
authors.lastname: Sekhar
authors.forename: Vijayakumar N
authors.initials: VN
authors.lastname: Sonar
authors.forename: Venkatraj
authors.initials: V
authors.lastname: Muthusamy
authors.forename: Soumya
authors.initials: S
authors.lastname: Sasi
authors.forename: Andrei
authors.initials: A
authors.lastname: Laszlo
authors.forename: Jamil
authors.initials: J
authors.lastname: Sawani
authors.forename: Nobuo
authors.initials: N
authors.lastname: Horikoshi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Higashikubo
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borrelli
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: James R
authors.initials: JR
authors.lastname: Lepock
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Roti Roti
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
mesh_terms: D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D004268:DNA-Binding Proteins / Q000378:metabolism; D045325:HCT116 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D011487:Protein Conformation / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D007211:Indoles; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors