0 216

Cited 8 times in

The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells

 Han-Soo Kim  ;  Ju Won Kim  ;  Jingu Gang  ;  Jing Wen  ;  Sang Seok Koh  ;  Jong Sung Koh  ;  Hyun-Ho Chung  ;  Si Young Song 
 Toxicology and Applied Pharmacology, Vol.215(3) : 317-329, 2006 
Journal Title
 Toxicology and Applied Pharmacology 
Issue Date
Animals ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Transformed ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Enzyme Inhibitors/pharmacology* ; Farnesyltranstransferase/antagonists & inhibitors* ; Genes, ras/genetics ; Imidazoles/pharmacology* ; Intestinal Mucosa/cytology ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/metabolism ; Piperazines/pharmacology* ; Pyrroles/pharmacology* ; Rats ; rhoB GTP-Binding Protein/metabolism
FTI ; ras ; Prenylation ; MAPK ; RhoB ; EGFR ; Apoptosis
LB42708 (LB7) and LB42908 (LB9) are pyrrole-based orally active farnesyltransferase inhibitors (FTIs) that have similar structures. The in vitro potencies of these compounds against FTase and GGTase I are remarkably similar, and yet they display different activity in apoptosis induction and morphological reversion of ras-transformed rat intestinal epithelial (RIE) cells. Both FTIs induced cell death despite K-ras prenylation, implying the participation of Ras-independent mechanism(s). Growth inhibition by these two FTIs was accompanied by G1 and G2/M cell cycle arrests in H-ras and K-ras-transformed RIE cells, respectively. We identified three key markers, p21CIP1/WAF1, RhoB and EGFR, that can explain the differences in the molecular mechanism of action between two FTIs. Only LB7 induced the upregulation of p21CIP1/WAF1 and RhoB above the basal level that led to the cell cycle arrest and to distinct morphological alterations of ras-transformed RIE cells. Both FTIs successfully inhibited the ERK and activated JNK in RIE/K-ras cells. While the addition of conditioned medium from RIE/K-ras reversed the growth inhibition of ras-transformed RIE cells by LB9, it failed to overcome the growth inhibitory effect of LB7 in both H-ras- and K-ras-transformed RIE cells. We found that LB7, but not LB9, decreased the expression of EGFRs that confers the cellular unresponsiveness to EGFR ligands. These results suggest that LB7 causes the induction of p21CIP1/WAF1 and RhoB and downregulation of EGFR that may serve as critical steps in the mechanism by which FTIs trigger irreversible inhibitions on the cell growth and apoptosis in ras-transformed cells.
Full Text
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Han Soo(김한수)
Song, Si Young(송시영) ORCID logo https://orcid.org/0000-0002-1417-4314
사서에게 알리기


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.