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

被引：24

作者：

Miklossy, Gabriella ^{[1
,2
]}

Youn, Ui Joung ^{[3
]}

Yue, Peibin ^{[1
,2
]}

Zhang, Mingming ^{[3
]}

Chen, Chih-Hong ^{[4
]}

Hilliard, Tyvette S. ^{[1
,2
]}

Paladino, David ^{[1
,2
]}

Li, Yifei ^{[4
]}

Choi, Justin ^{[4
]}

Sarkaria, Jann N. ^{[5
]}

Kawakami, Joel K. ^{[6
]}

Wongwiwatthananukit, Supakit ^{[3
]}

Chen, Yuan ^{[4
]}

Sun, Dianqing ^{[3
]}

Chang, Leng Chee ^{[3
]}

Turkson, James ^{[1
,2
]}

机构：

[1] Univ Hawaii Manoa, Univ Hawaii, Ctr Canc, Nat Prod & Expt Therapeut Program, Honolulu, HI 96813 USA

[2] Univ Hawaii Manoa, Univ Hawaii, Ctr Canc, Canc Biol Program, Honolulu, HI 96813 USA

[3] Univ Hawaii, Daniel K Inouye Coll Pharm, Dept Pharmaceut Sci, Hilo, HI 96720 USA

[4] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA

[5] Mayo Clin, Dept Radiat Oncol, Rochester, MN 55905 USA

[6] Chaminade Univ, Div Nat Sci & Math, Honolulu, HI 96816 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 19期

关键词：

SMALL-MOLECULE INHIBITOR; SESQUITERPENE LACTONES; GENE-REGULATION; CELL-TRANSFORMATION; VERNONIA-CINEREA; DRUG DISCOVERY; CANCER-CELLS; HUMAN BREAST; GROWTH; ACTIVATION;

D O I：

10.1021/acs.jmedchem.5b00686

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 alpha-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 a-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.

引用

页码：7734 / 7748

页数：15