Aszonapyrone A Isolated from Neosartorya spinosa IFM 47025 Inhibits the NF- κ B Signaling Pathway Activated by Expression of the Ependymoma-Causing Fusion Protein ZFTA-RELA

Abstract

Ependymoma is a rare and chemotherapy-resistant brain tumor, which has resulted in a delay in the development of drugs to treat it. A subclass of supratentorial ependymomas (ST-EPN), designated ST-EPN-zinc finger-translocation-associated (ZFTA, ST-EPN-ZFTA), exhibits the expression of a fusion protein comprising ZFTA and v- rel reticuloendotheliosis viral oncogene homolog A (RELA), an effector transcription factor of the nuclear factor-kappa B (NF- κ B) pathway (ZFTA-RELA). The expression of ZFTA-RELA results in the hyperactivation of the oncogenic NF- κ B signaling pathway, which ultimately leads to the development of ST-EPN-ZFTA. To identify inhibitors of the NF- κ B signaling pathway activated by the expression of ZFTA-RELA, we used a doxycycline-inducible ZFTA-RELA-expressing NF- κ B reporter cell line and found that extracts of the fungus Neosartorya spinosa IFM 47025 exhibited NF- κ B inhibitory activity. We identified eight compounds [aszonapyrone A ( 2 ), sartorypyrone A ( 3 ), epiheveadride ( 4 ), acetylaszonalenin ( 5 ), ( R )-benzodiazepinedione ( 6 ), aszonalenin ( 7 ), sartorypyrone E ( 8 ) and ( Z , Z )- N , N ’-(1,2-bis[(4-methoxyphenyl)methylene]-1,2-ethanediyl)bis-formamide ( 9 )] from N. spinosa IFM 47025 culture extract using a variety of chromatographic techniques. The structures of these compounds were identified through the analysis of various instrumental data (1D, 2D-NMR, MS, and optical rotation). The NF- κ B responsive reporter assay indicated that compounds 2 , 3 , 5 , 7 , and 9 exhibited inhibitory activity. We further evaluated the inhibitory activity of these compounds against the expression of endogenous NF- κ B responsive genes ( CCND1 , L1CAM , ICAM1 , and TNF ) and found that compound 2 showed significant inhibitory activity. Further studies are required to elucidate the mechanism of action of compound 2 , which may serve as a lead compound for the development of a novel therapy for ST-EPN-ZFTA.