Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells.

Authors:
Florian Kopp
Florian Kopp
Philipps-Universität Marburg
Germany
Adam Hermawan
Adam Hermawan
Universitas Gadjah Mada
Indonesia
Prajakta Shirish Oak
Prajakta Shirish Oak
Ludwig-Maximilians-Universität München
Germany
Vijay Kumar Ulaganathan
Vijay Kumar Ulaganathan
Max-Planck-Institute for Neurobiology
Germany
Annika Herrmann
Annika Herrmann
Eberhard Karls University
Germany
Nefertiti Elnikhely
Nefertiti Elnikhely
Max Planck Institute for Heart and Lung Research
Bad Nauheim | Germany
Chitra Thakur
Chitra Thakur
Eugene Applebaum College of Pharmacy and Health Sciences
Zhiguang Xiao
Zhiguang Xiao
University of Melbourne
Australia

Transl Oncol 2014 Dec;7(6):702-11

Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address:

Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)-specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition.

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http://dx.doi.org/10.1016/j.tranon.2014.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311025PMC
December 2014
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5 PubMed Central Citations(source)

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