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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 19 Pg. 7734-48 (Oct 08 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26331426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HSP110 Heat-Shock Proteins
• HSPH1 protein, human
• MAP1B protein, human
• Microtubule-Associated Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Trans-Activators
• Vimentin
• alpha Karyopherins
• karyopherin alpha 2
• Glucosephosphate Dehydrogenase
• TXNRD1 protein, human
• Thioredoxin Reductase 1

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Drug Evaluation, Preclinical (methods)
• Female
• Glioma (drug therapy, metabolism, pathology)
• Glucosephosphate Dehydrogenase (metabolism)
• HSP110 Heat-Shock Proteins (metabolism)
• Humans
• Magnetic Resonance Spectroscopy
• Mice, Nude
• Microtubule-Associated Proteins (metabolism)
• Molecular Docking Simulation
• Molecular Structure
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Structure-Activity Relationship
• Thioredoxin Reductase 1 (metabolism)
• Trans-Activators (metabolism)
• Vimentin (metabolism)
• Xenograft Model Antitumor Assays
• alpha Karyopherins (metabolism)