Identification of new shikonin derivatives as STAT3 inhibitors.

Abstract

The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.

• Authors: Han-Yue Qiu, Jiang-Yan Fu, Min-Kai Yang, Hong-Wei Han, Peng-Fei Wang, Ya-Han Zhang, Hong-Yan Lin, Cheng-Yi Tang, Jin-Liang Qi, Rong-Wu Yang, Xiao-Ming Wang, Hai-Liang Zhu, Yong-Hua Yang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 146 Pg. 74-86 (12 15 2017) ISSN: 1873-2968 [Electronic] England
• PMID: 29066190 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Naphthoquinones
• PMMB-187
• STAT3 Transcription Factor
• STAT3 protein, human
• Thiadiazoles
• shikonin

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Female
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Models, Molecular
• Molecular Structure
• Naphthoquinones (chemical synthesis, chemistry, pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Thiadiazoles (chemical synthesis, chemistry, pharmacology)