Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma.
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.
Gabriella
G
Miklossy
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo , Hilo 96720, Hawaii, United States.
Ui Joung
UJ
Youn
Peibin
P
Yue
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo , Hilo 96720, Hawaii, United States.
Mingming
M
Zhang
Department of Molecular Medicine, Beckman Research Institute of the City of Hope , Duarte 91010, California, United States.
Chih-Hong
CH
Chen
Tyvette S
TS
Hilliard
David
D
Paladino
Department of Molecular Medicine, Beckman Research Institute of the City of Hope , Duarte 91010, California, United States.
Yifei
Y
Li
Department of Molecular Medicine, Beckman Research Institute of the City of Hope , Duarte 91010, California, United States.
Justin
J
Choi
Department of Radiation Oncology, Mayo Clinic , Rochester 55905, Minnesota, United States.
Jann N
JN
Sarkaria
Division of Natural Sciences and Mathematics, Chaminade University , Honolulu 96816, Hawaii, United States.
Joel K
JK
Kawakami
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo , Hilo 96720, Hawaii, United States.
Supakit
S
Wongwiwatthananukit
Department of Molecular Medicine, Beckman Research Institute of the City of Hope , Duarte 91010, California, United States.
Yuan
Y
Chen
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo , Hilo 96720, Hawaii, United States.
Dianqing
D
Sun
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo , Hilo 96720, Hawaii, United States.
Leng Chee
LC
Chang
James
J
Turkson
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D028901:alpha Karyopherins / Q000378:metabolism
D000970:Antineoplastic Agents; D050957:HSP110 Heat-Shock Proteins; C097205:HSPH1 protein, human; C475491:MAP1B protein, human; D008869:Microtubule-Associated Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014746:Vimentin; D028901:alpha Karyopherins; C087978:karyopherin alpha 2; D005954:Glucosephosphate Dehydrogenase; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1