@article{pittir20626,
          volume = {292},
          number = {2},
           month = {February},
          author = {A Vogt and AS Wang and CS Johnson and JP Fabisiak and P Wipf and JS Lazo},
           title = {In vivo antitumor activity and induction of insulin-like growth factor- 1-resistant apoptosis by SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9},
         journal = {Journal of Pharmacology and Experimental Therapeutics},
           pages = {530 -- 537},
            year = {2000},
             url = {http://d-scholarship-dev.library.pitt.edu/20626/},
        abstract = {We previously showed that SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}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-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9 induces IGF-1- resistant apoptosis and kills tumor cells in vivo. In cultured murine 32D cells, SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}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-{\ensuremath{\alpha}}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-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9. Furthermore, IGF-1 receptor overexpression failed to protect cells against SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9-induced apoptosis. Kinetic analyses demonstrated that Cdc2 down- regulation after SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9 treatment preceded both apoptosis and loss of the IGF-1 receptor, indicating that loss of Cdc2 was a direct effect of SC- {\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9 treatment and not secondary to cell death. IGF-1 receptor autophosphorylation studies indicated that SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}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-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9 caused a dose- dependent decrease in clonogenic cell survival. The IC50 of SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9 was 35 mg/kg, comparable to 25 mg/kg carboplatin. The ability to induce IGF-1- resistant apoptosis distinguishes SC-{\ensuremath{\alpha}}{\ensuremath{\alpha}}{\ensuremath{\delta}}9 from other apoptosis-inducing agents and suggests compounds of this class deserve further study as potential anticancer agents.}
}