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

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

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

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,

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.

Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway. Publishing Authors By Initials

KR Sekhar,VN Sonar,V Muthusamy,S Sasi,A Laszlo,J Sawani,N Horikoshi,R Higashikubo,RG Bristow,MJ Borrelli,PA Crooks,JR Lepock,JL Roti Roti,ML Freeman,

For similar proteins: transcription factors research abstracts see: proteins: transcription factors research

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

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Cancer research

VOLUME: 67

Page Numbers: 695-701

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 15

MONTH: Jan

YEAR: 2007

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway. Keywords Mesh Terms:

KEYWORDS: Transcription Factors

MESH TERMS: metabolism

Chemical & Substance for Abstract: Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway. Information

Substance Name: heat shock transcription factor

Registry Number: 0

Grant and Affiliation Information for Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway.

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.

Country: United States

AGENCY: United States NCI

GRANT: P01 CA104457

ACRONYM: CA

MEDLINETA: Cancer Res

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