Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent

The Signal Transducer and Activator of Transcription 3 (STAT3) oncogene is a master regulator of many human cancers, and a well-recognized target for therapeutic intervention. A well known STAT3 inhibitor, S3I-201 (NSC 74859), is hypothesized to block STAT3 function in cancer cells by binding the ST...

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Bibliographic Details
Published in:Oncotarget 2016-04, Vol.7 (15), p.20669-20679
Main Authors: Ball, Daniel P, Lewis, Andrew M, Williams, Declan, Resetca, Diana, Wilson, Derek J, Gunning, Patrick T
Format: Article
Language:English
Subjects:
Alkylating Agents - pharmacology
Aminosalicylic Acids - pharmacology
Apoptosis - drug effects
Benzenesulfonates - pharmacology
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Proliferation - drug effects
Female
Humans
Research Paper
STAT3 Transcription Factor - antagonists & inhibitors
Tumor Cells, Cultured
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Summary:The Signal Transducer and Activator of Transcription 3 (STAT3) oncogene is a master regulator of many human cancers, and a well-recognized target for therapeutic intervention. A well known STAT3 inhibitor, S3I-201 (NSC 74859), is hypothesized to block STAT3 function in cancer cells by binding the STAT3 SH2 domain and disrupt STAT3 protein complexation events. In this study, liquid chromatography tandem mass spectrometry analysis revealed that STAT3, in the presence of S3I-201, showed a minimum of five specific sites of modification, cysteine's 108, 259, 367, 542, and 687. Moreover, a prepared fluorescently labeled chemical probe of S3I-201 (DB-6-055) revealed that S3I-201 non-specifically and globally alkylated intracellular proteins at concentrations consistent with S3I-201's reported IC50. These data are consistent with the hypothesis that S3I-201 is a sub-optimal probe for interrogating STAT3-related cell biology.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.7838