Document Detail


Inhibition of pancreatic adenocarcinoma cell growth by lovastatin.
MedLine Citation:
PMID:  1499946     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RAS protein (p21 ras) requires farnesyl (an intermediate of cholesterol synthesis) for activation. Activating mutations of K-ras gene have been detected in most human pancreatic adenocarcinomas. In the present study, the effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, the rate-limiting enzyme of cholesterol synthesis, on the growth of five pancreatic cancer cell lines (human-CAV, MIA Paca2, CAPAN2 and PANC1, and hamster-H2T) in vitro and of two cell lines (CAV and H2T) in vivo was examined. Inhibition of cell growth was observed with lovastatin doses at or above 2.5 micrograms/mL for H2T, CAV, MIA Paca2, and CAPAN2 or 10 micrograms/mL in PANC1. The H2T cell line was studied further to determine the reversibility of growth inhibition. Mevalonic acid (1 mmol/L) reversed lovastatin-induced inhibition of cell growth if it was added with lovastatin (2.5 micrograms/mL). Similarly, removal of lovastatin from the medium within 24 hours after treatment allowed recovery of cell growth. The effect of lovastatin on cell growth was irreversible after 48 hours of exposure. The survival fraction of H2T cells was markedly decreased by 1- or 24-hour exposure to 75 micrograms/mL but not to doses ranging from 0.5 to 60 micrograms/mL of lovastatin. Growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice was inhibited by a subcutaneous infusion of lovastatin (50 micrograms/h). These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for growth of pancreatic cancer cells and suggest that lovastatin should be further examined as a potential therapeutic agent for pancreatic cancer.
Authors:
S Sumi; R D Beauchamp; C M Townsend; T Uchida; M Murakami; S Rajaraman; J Ishizuka; J C Thompson
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gastroenterology     Volume:  103     ISSN:  0016-5085     ISO Abbreviation:  Gastroenterology     Publication Date:  1992 Sep 
Date Detail:
Created Date:  1992-09-15     Completed Date:  1992-09-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  982-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Surgery, University of Texas Medical Branch, Galveston.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Division / drug effects
Cell Survival / drug effects
Cricetinae
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Lovastatin / antagonists & inhibitors,  pharmacology*
Mevalonic Acid / pharmacology
Mice
Mice, Nude
Pancreatic Neoplasms / pathology*
Time Factors
Transplantation, Heterologous
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
5R37 DK 15241/DK/NIDDK NIH HHS; P01 DK 35608/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
150-97-0/Mevalonic Acid; 75330-75-5/Lovastatin

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


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