Abstract 5432: Spirooxindole derivative (SOID-8) inhibits proliferation and induces apoptosis by blocking JAK2/STAT3 signaling in melanoma cells

Abstract

Abstract Melanoma is the most malignant skin cancer, and is generally refractory to current chemotherapy, so new treatment strategies are needed. In this study, we show that a spirooxindole derivative, SOID-8, which is a synthetic analogue inspired by the natural product, spirotryprostatin B, significantly inhibits cell proliferation in four established human melanoma cell lines. This decrease in viability of A2058 and A375 melanoma cells is associated with apoptosis, as confirmed by an increase in poly(ADP-ribose)polymerase cleavage. In addition, the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, is downregulated and correlated with SOID-8 induced apoptosis. Morevoer, SOID-8 inhibits tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in both melanoma cell lines in a dose- and time-dependent manner. In contrast, phosphorylation of AKT (protein kinase B) is reduced by SOID-8 only at high concentrations, and phosphorylation of MAPK (extracellular signal-regulated kinase 1/2) is not inhibited at all by SOID-8 in these cells. Furthermore, this compound decreases the phosphorylated Janus kinase-2 (JAK2) levels in a dose- and time-dependent fashion. Importantly, SOID-8 inhibits phosphorylation of STAT3 and JAK2 induced by IL-6 stimulation in A2058 and A375 cells. In summary, our results show that SOID-8 selectively blocks JAK2/STAT3 signaling as well as expression of apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in melanoma cells. These data suggest that antitumor activity of the spirooxindole derivative SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells and is a promising small molecule candidate for melanoma therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5432. doi:10.1158/1538-7445.AM2011-5432