title: In vivo antitumor activity and induction of insulin-like growth factor-1-resistant apoptosis by SC-alphaalphadelta9.
abstract: We previously showed that SC-alphaalphadelta9 (4-(benzyl-(2-[(2, 5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylami no 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-alphaalphadelta9 induces IGF-1-resistant apoptosis and kills tumor cells in vivo. In cultured murine 32D cells, SC-alphaalphadelta9 induced concentration-dependent apoptosis that was blocked by ectopic Bcl-2 expression. No apoptosis was detected in 32D cells treated with the congener SC-alpha109, 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-alphaalphadelta9. Furthermore, IGF-1 receptor overexpression failed to protect cells against SC-alphaalphadelta9-induced apoptosis. Kinetic analyses demonstrated that Cdc2 down-regulation after SC-alphaalphadelta9 treatment preceded both apoptosis and loss of the IGF-1 receptor, indicating that loss of Cdc2 was a direct effect of SC-alphaalphadelta9 treatment and not secondary to cell death. IGF-1 receptor autophosphorylation studies indicated that SC-alphaalphadelta9 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-alphaalphadelta9 caused a dose-dependent decrease in clonogenic cell survival. The IC(50) of SC-alphaalphadelta9 was 35 mg/kg, comparable to 25 mg/kg carboplatin. The ability to induce IGF-1-resistant apoptosis distinguishes SC-alphaalphadelta9 from other apoptosis-inducing agents and suggests compounds of this class deserve further study as potential anticancer agents.
authors.affiliation: Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vogt
authors.forename: A S
authors.initials: AS
authors.lastname: Wang
authors.forename: C S
authors.initials: CS
authors.lastname: Johnson
authors.forename: J P
authors.initials: JP
authors.lastname: Fabisiak
authors.forename: P
authors.initials: P
authors.lastname: Wipf
authors.forename: J S
authors.initials: JS
authors.lastname: Lazo
mesh_terms: D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016190:Carboplatin / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000613:Aminobutyrates; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007377:Interleukin-3; D010080:Oxazoles; C404149:SC alpha109; C115707:SC-alphaalphadelta9; D007334:Insulin-Like Growth Factor I; D005047:Etoposide; D016190:Carboplatin; D017526:Receptor, IGF Type 1