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
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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.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
|
Date: |
1 February 2000 |
Date Type: |
Publication |
Journal or Publication Title: |
Journal of Pharmacology and Experimental Therapeutics |
Volume: |
292 |
Number: |
2 |
Page Range: |
530 - 537 |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
0022-3565 |
MeSH Headings: |
Aminobutyrates--pharmacology; Animals; Antineoplastic Agents--pharmacology; Antineoplastic Agents--therapeutic use; Apoptosis--drug effects; Blotting, Western; Carboplatin--therapeutic use; Cell Cycle Proteins--genetics; Cell Transformation, Neoplastic--drug effects; Dose-Response Relationship, Drug; Down-Regulation--drug effects; Drug Interactions; Etoposide--pharmacology; Inhibitory Concentration 50; Insulin-Like Growth Factor I--pharmacology; Interleukin-3--pharmacology; Mice; Oxazoles--pharmacology; Oxazoles--therapeutic use; Receptor, IGF Type 1--genetics; Time Factors; Tumor Cells, Cultured; Tumor Stem Cell Assay |
PubMed ID: |
10640289 |
Date Deposited: |
27 Feb 2014 16:51 |
Last Modified: |
12 Jun 2021 20:55 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/20626 |
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