%A A Vogt
%A AS Wang
%A CS Johnson
%A JP Fabisiak
%A P Wipf
%A JS Lazo
%J Journal of Pharmacology and Experimental Therapeutics
%T In vivo antitumor activity and induction of insulin-like growth factor- 1-resistant apoptosis by SC-???9
%X We previously showed that SC-???9 {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-???9 induces IGF-1- resistant apoptosis and kills tumor cells in vivo. In cultured murine 32D cells, SC-???9 induced concentration-dependent apoptosis that was blocked by ectopic Bcl-2 expression. No apoptosis was detected in 32D cells treated with the congener SC-?109, 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-???9. Furthermore, IGF-1 receptor overexpression failed to protect cells against SC-???9-induced apoptosis. Kinetic analyses demonstrated that Cdc2 down- regulation after SC-???9 treatment preceded both apoptosis and loss of the IGF-1 receptor, indicating that loss of Cdc2 was a direct effect of SC- ???9 treatment and not secondary to cell death. IGF-1 receptor autophosphorylation studies indicated that SC-???9 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-???9 caused a dose- dependent decrease in clonogenic cell survival. The IC50 of SC-???9 was 35 mg/kg, comparable to 25 mg/kg carboplatin. The ability to induce IGF-1- resistant apoptosis distinguishes SC-???9 from other apoptosis-inducing agents and suggests compounds of this class deserve further study as potential anticancer agents.
%N 2
%P 530 - 537
%V 292
%D 2000
%L pittir20626