Novel Sesquiterpene Lactones Derived From Vernonia Cinerea Inhibit Stat3 Activity And Suppress Human Glioblastoma Phenotype

Constitutively-active STAT3 is prevalent in glioblastoma multiforme, breast cancer and many other human tumors and is a valid target for the discovery of novel anticancer therapeutics. Screening of whole plant extracts from Vernonia cinerea identified sesquiterpene lactones of the hirsutinolide type that inhibit aberrant STAT3 activity and suppress human glioma phenotype in vitro and in vivo. Compounds 6, 10, 20 and 22 suppressed the viability of human glioma, U251MG cells that harbor aberrantly-active STAT3, with IC 50 of 2.4-6 µM. Treatment of U251MG cells with any of the four natural product agents inhibited STAT3 phosphorylation in a time-dependent manner, with little or no effects on pErk1/2 and pAkt levels. By contrast, other hirsutinolides, including compounds 8, 9, 11, 18, 19 and 28 showed modest or undetectable effects on U251MG cell viability or on pSTAT3 in U251MG cells. Furthermore, treatment with compounds 6, 10 or 22 had moderate or no effects on phospho-JAK2 or phospho-Src or on the protein tyrosine phosphatase, PTP1B level, as measured by Western blot. Moreover, combined treatment with sodium orthovanadate had minimal effect on compound 6-induced decrease in pSTAT3 levels, altogether suggesting that protein tyrosine phosphatases are less likely to be the primary mechanism for down-regulation of pSTAT3 in treated U251MG cells. By contrast, co-treatment with compund 6 repressed the robust induction of pSTAT3 levels by sodium orthovanadate. Furthermore, treatment with compound 6, 10, 20 or 22 inhibited colony formation and the migration of U251MG cells in vitro, and repressed the expression of STAT3 regulated genes, including Mcl-1 in U251MG cells. In vivo anti-tumor efficacy studies of compound 6 revealed dose-dependent inhibition of the growth of human glioma tumor xenografts in mice. Our studies have identified natural product-based small molecules that potently inhibit STAT3 activity and preferentially induce antitumor cell effects in vitro and antitumor response in vivo against human glioma. Citation Format: Gabriella Miklossy, Ui Joung Youn, Peibin Yue, Leng Chee Chang, James Turkson. Novel sesquiterpene lactones derived from Vernonia cinerea inhibit STAT3 activity and suppress human glioblastoma phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2694. doi:10.1158/1538-7445.AM2014-2694