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Open Access Highly Accessed Research article

Salinomycin increases chemosensitivity to the effects of doxorubicin in soft tissue sarcomas

Sven-T Liffers1*, Daniel J Tilkorn2, Ingo Stricker1, Christoph Günter Junge1, Sammy Al-Benna2, Markus Vogt1, Berlinda Verdoodt1, Hans-U Steinau2, Andrea Tannapfel1, Iris Tischoff1 and Alireza Mirmohammadsadegh1

Author Affiliations

1 Institute of Pathology, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany

2 Department of Plastic Surgery, Burn Center, Hand Surgery, Sarcoma Reference Center, BG University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany

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BMC Cancer 2013, 13:490  doi:10.1186/1471-2407-13-490

Published: 21 October 2013

Abstract

Background

Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed.

Methods

To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-κB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation.

Results

The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-κB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes.

Conclusions

Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.

Keywords:
Apoptosis; Salinomycin; Doxorubicin; Malignant soft tissue tumors; Chemotherapy