Abstract

Multidrug resistance presents an obstacle in cancer treatment. Among numerous combative strategies, collateral sensitivity (CS) drugs have opened a new avenue to defeat cancer by exploiting selective toxicity against multidrug-resistant (MDR) cancer. In the present study, a clinically used synthetic steroid hormone, danazol, was investigated for its CS properties and cytotoxic mechanisms. Compared with natural hormones, danazol possessed a stronger selective cytotoxicity against MDR cancer cells. Danazol induced the arrest of MDR cancer cells at the G2/M phase and caspase-8–related early apoptosis. Furthermore, in MDR cancer cells, danazol reduced STAT3 phosphorylation as well as the expression of STAT3-regulated genes involved in cell survival, such as c-Myc, CDC25, and CDK1. Danazol also upregulated the cell cycle inhibitor p21 in MDR cancer cells. Supporting the experimental results, docking studies have revealed that danazol can likely bind favourably with STAT3. Taken together, our results suggest that danazol exerts a CS effect by inhibiting the STAT3 pathway in MDR cancer cells and thus provides a possible solution for MDR cancers.

Details

Title
Danazol mediates collateral sensitivity via STAT3/Myc related pathway in multidrug-resistant cancer cells
Author
Chang, Ying-Tzu 1 ; Yu-Ning, Teng 2 ; Kun-I Lin 3 ; Wang, Charles C N 4   VIAFID ORCID Logo  ; Morris-Natschke, Susan L 5 ; Kuo-Hsiung, Lee 6 ; Chin-Chuan Hung 7 

1  Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC 
2  Department of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, ROC 
3  Department of Obstetrics and Gynecology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan, ROC; Department of Cosmetic Science, Providence University, Taichung, Taiwan, ROC 
4  Department of Biomedical Informatics, Asia University, Wufeng, Taichung, Taiwan, ROC 
5  Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, North Carolina, United States 
6  Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, North Carolina, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan, ROC 
7  Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC; Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan, ROC 
Pages
1-11
Publication year
2019
Publication date
Aug 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-48169-2
ProQuest document ID
2272204025
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.