Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma

Gabriella Miklossy, Ui Joung Youn, Peibin Yue, Mingming Zhang, Chih Hong Chen, Tyvette S. Hilliard, David Paladino, Yifei Li, Justin Choi, Jann N Sarkaria, Joel K. Kawakami, Supakit Wongwiwatthananukit, Yuan Chen, Dianqing Sun, Leng Chee Chang, James Turkson

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Abstract

We report that hirsutinolide series, 6, 7, 10, 11, 20, and 22, and the semisynthetic analogues, 30, 31, 33, and 36, inhibit constitutively active signal transducer and activator of transcription (Stat)3 and malignant glioma phenotype. A position 13 lipophilic ester group is required for activity. Molecular modeling and nuclear magnetic resonance structural analyses reveal direct hirsutinolide:Stat3 binding. One-hour treatment of cells with 6 and 22 also upregulated importin subunit α-2 levels and repressed translational activator GCN1, microtubule-associated protein (MAP)1B, thioredoxin reductase (TrxR)1 cytoplasmic isoform 3, glucose-6-phosphate 1-dehydrogenase isoform a, Hsp105, vimentin, and tumor necrosis factor α-induced protein (TNAP)2 expression. Active hirsutinolides inhibited anchorage-dependent and three-dimensional spheroid growth, survival, and migration of human glioma lines and glioma patients tumor-derived xenograft cells harboring constitutively active Stat3. Oral gavage delivery of 6 or 22 inhibited human glioma tumor growth in subcutaneous mouse xenografts. The inhibition of Stat3 signaling represents part of the hirsutinolide-mediated mechanisms to induce antitumor effects.

Original languageEnglish (US)
Pages (from-to)7734-7748
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number19
DOIs
StatePublished - Oct 8 2015

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Miklossy, G., Youn, U. J., Yue, P., Zhang, M., Chen, C. H., Hilliard, T. S., Paladino, D., Li, Y., Choi, J., Sarkaria, J. N., Kawakami, J. K., Wongwiwatthananukit, S., Chen, Y., Sun, D., Chang, L. C., & Turkson, J. (2015). Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma. Journal of Medicinal Chemistry, 58(19), 7734-7748. https://doi.org/10.1021/acs.jmedchem.5b00686