eprintid: 20626
rev_number: 23
userid: 1419
dir: disk0/00/02/06/26
datestamp: 2014-02-27 16:51:36
lastmod: 2021-06-12 20:55:13
status_changed: 2014-02-27 16:51:36
type: article
metadata_visibility: show
item_issues_count: 0
eprint_status: archive
creators_name: Vogt, A
creators_name: Wang, AS
creators_name: Johnson, CS
creators_name: Fabisiak, JP
creators_name: Wipf, P
creators_name: Lazo, JS
creators_email: 
creators_email: 
creators_email: 
creators_email: fabs@pitt.edu
creators_email: pwipf@pitt.edu
creators_email: 
creators_id: 
creators_id: 
creators_id: 
creators_id: FABS
creators_id: PWIPF
creators_id: 
title: In vivo antitumor activity and induction of insulin-like growth factor- 1-resistant apoptosis by SC-ααδ9
ispublished: pub
divisions: sch_as_chemistry
full_text_status: public
abstract: We previously showed that SC-ααδ9 {4-(benzyl-(2-[(2,5-diphenyl- oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid} is a novel antiphosphatase agent that selectively inhibits the growth of transformed cells in culture and affects elements of insulin-like growth factor-1 (IGF-1) signaling. We now show that SC-ααδ9 induces IGF-1- resistant apoptosis and kills tumor cells in vivo. In cultured murine 32D cells, SC-ααδ9 induced concentration-dependent apoptosis that was blocked by ectopic Bcl-2 expression. No apoptosis was detected in 32D cells treated with the congener SC-α109, which lacks the ability to disrupt IGF-1 signaling. After interleukin-3 withdrawal or etoposide treatment, exogenous IGF-1 prevented apoptosis and elevated levels of Cdc2, a biochemical indicator of a functional IGF-1 receptor pathway. In contrast, exogenous IGF- 1 did not prevent apoptosis or loss of Cdc2 expression caused by SC-ααδ9. Furthermore, IGF-1 receptor overexpression failed to protect cells against SC-ααδ9-induced apoptosis. Kinetic analyses demonstrated that Cdc2 down- regulation after SC-ααδ9 treatment preceded both apoptosis and loss of the IGF-1 receptor, indicating that loss of Cdc2 was a direct effect of SC- ααδ9 treatment and not secondary to cell death. IGF-1 receptor autophosphorylation studies indicated that SC-ααδ9 did not interact directly with the IGF-1 receptor nor bind to the growth factor itself, suggesting a site of action distal to the IGF-1 receptor. In the SCCVII murine tumor model, a single i.p. injection of SC-ααδ9 caused a dose- dependent decrease in clonogenic cell survival. The IC50 of SC-ααδ9 was 35 mg/kg, comparable to 25 mg/kg carboplatin. The ability to induce IGF-1- resistant apoptosis distinguishes SC-ααδ9 from other apoptosis-inducing agents and suggests compounds of this class deserve further study as potential anticancer agents.
date: 2000-02-01
date_type: published
publication: Journal of Pharmacology and Experimental Therapeutics
volume: 292
number: 2
pagerange: 530 - 537
refereed: TRUE
issn: 0022-3565
pmid: 10640289
mesh_headings: Aminobutyrates--pharmacology
mesh_headings: Animals
mesh_headings: Antineoplastic Agents--pharmacology
mesh_headings: Antineoplastic Agents--therapeutic use
mesh_headings: Apoptosis--drug effects
mesh_headings: Blotting, Western
mesh_headings: Carboplatin--therapeutic use
mesh_headings: Cell Cycle Proteins--genetics
mesh_headings: Cell Transformation, Neoplastic--drug effects
mesh_headings: Dose-Response Relationship, Drug
mesh_headings: Down-Regulation--drug effects
mesh_headings: Drug Interactions
mesh_headings: Etoposide--pharmacology
mesh_headings: Inhibitory Concentration 50
mesh_headings: Insulin-Like Growth Factor I--pharmacology
mesh_headings: Interleukin-3--pharmacology
mesh_headings: Mice
mesh_headings: Oxazoles--pharmacology
mesh_headings: Oxazoles--therapeutic use
mesh_headings: Receptor, IGF Type 1--genetics
mesh_headings: Time Factors
mesh_headings: Tumor Cells, Cultured
mesh_headings: Tumor Stem Cell Assay
chemical_names: Aminobutyrates
chemical_names: Antineoplastic Agents
chemical_names: Cell Cycle Proteins
chemical_names: Interleukin-3
chemical_names: Oxazoles
chemical_names: SC alpha109
chemical_names: SC-alphaalphadelta9
chemical_names: Insulin-Like Growth Factor I
chemical_names: Etoposide
chemical_names: Carboplatin
chemical_names: Receptor, IGF Type 1
citation:   Vogt, A and Wang, AS and Johnson, CS and Fabisiak, JP and Wipf, P and Lazo, JS  (2000) In vivo antitumor activity and induction of insulin-like growth factor- 1-resistant apoptosis by SC-ααδ9.  Journal of Pharmacology and Experimental Therapeutics, 292 (2).  530 - 537.  ISSN 0022-3565     
document_url: http://d-scholarship-dev.library.pitt.edu/20626/1/licence.txt