Abstract 3836: Enhancement of doxorubicin cytotoxicity in breast cancer by NIM811, A non-immunosuppressive cyclosporine A analog

Abstract

Abstract Cyclophilin A (CypA) is a member of the immunophilin family of peptidyl prolyl isomerases (PPI) that catalyze the cis-trans interconversion of proline imide bonds of peptides. In this role, cyclophilins have been found to function as signaling switches, regulating the activity of receptors, kinases and transcription factors. The PPI activity of CypA is inhibited by the immunosuppressive drug cyclosporine A (CsA), and in turn the CypA-CsA complex inhibits calcineurin-mediated NFAT activation. Our laboratory has demonstrated that CypA is necessary for the prolactin (PRL)-induced activation of Jak2/Stat5 signaling and gene expression (Cancer Res 68:7769, 2008). In addition, we have also shown that CsA inhibits the in vitro and in vivo growth and progression of both ER+ and ER- breast cancer cell lines. Here, we show that the non-immunosuppressive CsA analog NIM811 blocked PRL-stimulated activation of the Jak2/Stat5, PI3K/AKT and MAPK pathways in T47D cells. NIM811 also inhibited ER+, ER-, and Her2+ breast cancer cell proliferation, survival, motility and anchorage independent growth in a dose-dependent manner. NIM811 inhibited PRL induced gene expression, such as CISH and Cyclin D1. NIM811 also blocked the PRL-induced association between Stat5 and cMyb, and at higher doses, triggered PARP cleavage and activate Caspase 3. Furthermore, NIM811 increased the effects of doxorubicin in inhibiting monolayer cell growth and soft agar colony growth in vitro. In vivo, NIM811 alone significantly induced the primary tumor central necrosis and inhibited lymph node metastasis; combining NIM811 with a low dose of doxorubicin significantly inhibited MDA-MB-231 breast cancer xenograft tumor growth and distant organ metastasis. In summary, these results indicate that non-immunosuppressive cyclophilin inhibitor NIM811 has significant potential as both a single agent or in combination with cytotoxic agents for breast cancer therapy. 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 3836. doi:1538-7445.AM2012-3836