XZH-5 inhibits STAT3 phosphorylation and enhances the cytotoxicity of chemotherapeutic drugs in human breast and pancreatic cancer cells.
Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in breast and pancreatic cancer. Inhibiting constitutive STAT3 signaling represents a promising molecular target for therapeutic approach. Using structure-based design, we developed a non-peptide cell-permeable, small molecule, termed as XZH-5, which targeted STAT3 phosphorylation. XZH-5 was found to inhibit STAT3 phosphorylation (Tyr705) and induce apoptosis in human breast and pancreatic cancer cell lines expressing elevated levels of phosphorylated STAT3. XZH-5 could also inhibit interleukin-6-induced STAT3 phosphorylation in cancer cell lines expressing low phosphorylated STAT3. Inhibition of STAT3 signaling by XZH-5 was confirmed by the down-regulation of downstream targets of STAT3, such as Cyclin D1, Bcl-2, and Survivin at mRNA level. In addition, XZH-5 inhibited colony formation, cell migration, and enhanced the cytotoxicity of chemotherapeutic drugs when combined with Doxorubicin or Gemcitabine. Our results indicate that XZH-5 may be a potential therapeutic agent for breast and pancreatic cancers with constitutive STAT3 signaling.
Department of Pediatrics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China. aiguoliu20@yahoo.com.cn
Aiguo
A
Liu
Yan
Y
Liu
Zhigang
Z
Jin
Qun
Q
Hu
Li
L
Lin
David
D
Jou
Jing
J
Yang
Zhenghu
Z
Xu
Hong
H
Wang
Chenglong
C
Li
Jiayuh
J
Lin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000077022:Survivin; C560270:XZH-5 compound; D019938:Cyclin D1; D006639:Histidine