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 language | English (US) |
|---|---|
| Pages (from-to) | 7734-7748 |
| Number of pages | 15 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 58 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 8 2015 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma. / Miklossy, Gabriella; Youn, Ui Joung; Yue, Peibin; Zhang, Mingming; Chen, Chih Hong; Hilliard, Tyvette S.; Paladino, David; Li, Yifei; Choi, Justin; Sarkaria, Jann N; Kawakami, Joel K.; Wongwiwatthananukit, Supakit; Chen, Yuan; Sun, Dianqing; Chang, Leng Chee; Turkson, James.
In: Journal of Medicinal Chemistry, Vol. 58, No. 19, 08.10.2015, p. 7734-7748.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma
AU - Miklossy, Gabriella
AU - Youn, Ui Joung
AU - Yue, Peibin
AU - Zhang, Mingming
AU - Chen, Chih Hong
AU - Hilliard, Tyvette S.
AU - Paladino, David
AU - Li, Yifei
AU - Choi, Justin
AU - Sarkaria, Jann N
AU - Kawakami, Joel K.
AU - Wongwiwatthananukit, Supakit
AU - Chen, Yuan
AU - Sun, Dianqing
AU - Chang, Leng Chee
AU - Turkson, James
PY - 2015/10/8
Y1 - 2015/10/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84943788983&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943788983&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b00686
DO - 10.1021/acs.jmedchem.5b00686
M3 - Article
C2 - 26331426
AN - SCOPUS:84943788983
VL - 58
SP - 7734
EP - 7748
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 19
ER -