Vol. 292, Issue 2, 530-537, February 2000

In Vivo Antitumor Activity and Induction of Insulin-Like Growth Factor-1-Resistant Apoptosis by SC-9¹

Andreas Vogt, Angela S. Wang, Candace S. Johnson , James P. Fabisiak , Peter Wipf and John S. Lazo

Departments of Pharmacology (A.V., A.S.W., C.S.J., J.P.F.), Chemistry (P.W., J.S.L.), Environmental and Occupational Health (J.P.F.), and the University of Pittsburgh Cancer Institute (C.S.J., P.W., J.S.L.), University of Pittsburgh, Pittsburgh, Pennsylvania.

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.