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
Gabriella MiklossyJames Turkson

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.

References

May 1, 1985·Molecular and Cellular Biology·P J JohnsonD Shalloway
Sep 12, 1997·Science·J E Darnell
Apr 16, 1998·The Journal of Biological Chemistry·M IchibaT Hirano
Jun 13, 2000·Oncogene·T BowmanR Jove
Jun 29, 2002·European Journal of Endocrinology·Domenico RubelloBrahm Shapiro
Feb 18, 2004·Nature Reviews. Cancer·Hua Yu, Richard Jove
Sep 24, 2004·Molecular & Cellular Proteomics : MCP·Philip L RossDarryl J Pappin
Oct 8, 2004·Expert Opinion on Therapeutic Targets·James Turkson
Apr 28, 2007·Proceedings of the National Academy of Sciences of the United States of America·Khandaker SiddiqueeJames Turkson
Feb 6, 2008·Cancer Imaging : the Official Publication of the International Cancer Imaging Society·K A Miles
Dec 31, 2008·Journal of Biomolecular NMR·Isabel AyalaJérôme Boisbouvier
Jun 27, 2009·Science·Daniel J GoughDavid E Levy
Oct 24, 2009·Nature Reviews. Cancer·Hua YuRichard Jove
Jul 3, 2010·ACS Medicinal Chemistry Letters·Jianyong ChenShaomeng Wang
Jan 21, 2012·Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia·Yaming XuFuxue Chen
Apr 26, 2012·Journal of Biomolecular NMR·Weidong HuYuan Chen
May 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Xiaolei ZhangJames Turkson
Aug 2, 2012·Bioorganic & Medicinal Chemistry Letters·Ui Joung YounLeng Chee Chang
Mar 15, 2013·Neuro-oncology·Maike PriesterJakob Weissenberger
Aug 2, 2013·Nature Reviews. Drug Discovery·Gabriella MiklossyJames Turkson
Jun 13, 2015·Natural Product Reports·You YangBiao Yu

❮ Previous
Next ❯

Citations

Oct 11, 2017·Phytotherapy Research : PTR·Phisit PouyfungPornpimol Rongnoparut
Feb 2, 2019·Current Medicinal Chemistry·Vasco BrancoCristina Carvalho
Mar 1, 2019·Journal of Medicinal Chemistry·Shaoyong LuJian Zhang
Aug 15, 2019·Journal of Natural Products·Mengke ZhangLeng Chee Chang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

Cancer Imaging

Imaging techniques, including CT and MR, have become essential to tumor detection, diagnosis, and monitoring. Here is the latest research on cancer imaging.

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.