Document Detail

Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines.
MedLine Citation:
PMID:  10484067     Owner:  NLM     Status:  MEDLINE    
We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.
J T Lim; G A Piazza; E K Han; T M Delohery; H Li; T S Finn; R Buttyan; H Yamamoto; G J Sperl; K Brendel; P H Gross; R Pamukcu; I B Weinstein
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  58     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1999 Oct 
Date Detail:
Created Date:  1999-09-17     Completed Date:  1999-09-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1097-107     Citation Subset:  IM    
Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
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MeSH Terms
Androgens / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Antineoplastic Agents / pharmacology*
Cell Division / drug effects
Cyclooxygenase Inhibitors / pharmacology
Drug Screening Assays, Antitumor
Prostaglandin-Endoperoxide Synthases / metabolism
Prostatic Neoplasms / drug therapy*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Sulindac / analogs & derivatives,  pharmacology*
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Androgens; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Antineoplastic Agents; 0/Cyclooxygenase Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 32004-67-4/sulindac sulfide; 38194-50-2/Sulindac; 59864-04-9/sulindac sulfone; EC Synthases

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