Abstract 1804: Novel gold derivatives of thiosugars potently inhibit p-STAT3 and downregulate HIF-1α in ependymomas

Abstract

Abstract Ependymoma is the third most common brain tumor in children, representing 5% of all CNS malignancies with an overall survival ranging from 24% to 75% at 5 years. Although auranofin (AF), a gold containing antirheumatic compound, has been tested for a variety of human cancers, the true potential of this compound or its related compounds as anticancer agents has not been fully explored for human cancer. However, recent observations identifying proteasome inhibition and alterations in the JAK/STAT signaling pathways as primary targets for gold compounds in several human cancers indicate that such compounds could be effective anticancer drugs providing a unique mechanism of action. We have recently designed several auranofin analogs (WP1527, WP1528, WP1529, WP1530, WP1531, WP1532, WP1533, WP1534, WP1546, and WP1547) and found that selected AF analogs (WP1529 and WP1532) markedly inhibit the proliferation of BT-58 and 58-10F human ependymoma cell lines. We discovered that ependymoma cell lines were more sensitive to AF than tested glioma cell lines and furthermore selected new analogs more potently inhibited BT-58 ependymoma cell proliferation than parental compound AF. Further analysis demonstrated that auranofin can potently (0.5 µM −1µM) block either constitutively activated or cytokine induced p- STAT3. Anticancer activity of these synthesized analogs has also been assessed in other tumor types including cutaneous T-cell lymphoma (CTCL) and melanoma. Our studies led to discovery of significantly more potent auranofin analogs and highly promising preliminary data warrant further studies to validated clinical potential of lead compound in ependymoma models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1804. doi:1538-7445.AM2012-1804