Document Detail


Clotrimazole induces a late G1 cell cycle arrest and sensitizes glioblastoma cells to radiation in vitro.
MedLine Citation:
PMID:  20724915     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tumor cells are characterized by their high rate of glycolysis and clotrimazole has been shown to disrupt the glycolysis pathway thereby arresting the cells in the G1 cell cycle phase. Herein, we present data to support our hypothesis that clotrimazole arrests tumor cells in a radiosensitizing, late G1 phase. The effects of clotrimazole were studied using the glioblastoma cell line, U-87 MG. Flow cytometry was used to analyze cell cycle redistribution and induction of apoptosis. Immunoblots were probed to characterize a late G1 cell cycle arrest. Nuclear and cytoplasmic fractions were collected to follow the clotrimazole-induced translocation of hexokinase II. Clonogenic assays were designed to determine the radiosensitizing effect by clotrimazole. Our studies have shown a dose-dependent and time-dependent clotrimazole arrest in a late G1 cell cycle phase. Concurrent with the late G1 arrest, we observed an overexpression of p27 along with a decreased expression of p21, cyclin-dependent kinase 1, cyclin-dependent kinase 4, and cyclin D. Clotrimazole induced the translocation of mitochondrial-bound hexokinase II to the cytoplasm and the release of cytochrome c into the cytoplasm. Clotrimazole-induced apoptosis was enhanced when combined with radiation. Clotrimazole was shown to sensitize tumor cells to radiation when the cells were irradiated for 18 h post-clotrimazole treatment. The disruption of the glycolysis pathway by clotrimazole leads to cell cycle arrest of U-87 MG cells in the radiosensitizing late G1 phase. The use of clotrimazole as a radiosensitizing agent for cancer treatment is novel and may have broad therapeutic applications.
Authors:
Hui Liu; Yufeng Li; Kevin P Raisch
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  21     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-02     Completed Date:  2010-12-22     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  841-9     Citation Subset:  IM    
Affiliation:
Departments of Radiation Oncology, University of Alabama at Birmingham, 35294, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Cell Line, Tumor
Clotrimazole / administration & dosage,  pharmacology*
Combined Modality Therapy
Dose-Response Relationship, Drug
Flow Cytometry
G1 Phase / drug effects*
Gene Expression Regulation, Neoplastic / drug effects
Glioblastoma / drug therapy*,  pathology,  radiotherapy
Glycolysis / drug effects
Humans
Immunoblotting
Radiation-Sensitizing Agents / administration & dosage,  pharmacology*
Time Factors
Grant Support
ID/Acronym/Agency:
P30 AR048311/AR/NIAMS NIH HHS; P30 AR48311/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Radiation-Sensitizing Agents; 23593-75-1/Clotrimazole

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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