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In vivo antitumor activity and induction of insulin-like growth factor- 1-resistant apoptosis by SC-ααδ9

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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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vogt, A
Wang, AS
Johnson, CS
Fabisiak, JPfabs@pitt.eduFABS
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
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: 22 Jun 2021 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/20626

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