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

Abstract

BackgroundChemotherapy 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.MethodsTo 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.ResultsThe 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.ConclusionsSalinomycin 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.

The nisin improves broiler chicken growth performance and interacts with salinomycin in terms of gastrointestinal tract microbiota composition

“…in broiler nutrition worldwide. The synergistic effects of this coccidiostat and other substances such as polymyxin B and doxorubicin were observed by Ogita et al (2009) and Liffers et al (2013). However, there are limited data concerning the impact of nisin and salinomycin combination on broiler GIT microbial ecology.…”

Co-Eradication of Breast Cancer Cells and Cancer Stem Cells by Cross-Linked Multilamellar Liposomes Enhances Tumor Treatment

“…Previous studies proposed that CSCs harbor innate resistance mechanisms to traditional chemotherapeutics, like doxorubicin, resulting in cancer relapse 11,14,36 . CSCs some of these survival mechanisms include stronger DNA repair capability, overexpression of efflux (ABC) transporters, increased antiapoptotic factors, and a slower proliferation rate compared to fast dividing cancer cells 5,8 .…”

“…A new approach to target these CSCs has long been desired, and the therapeutic advantage of salinomycin and its potential role as a CSC-targeted inhibitor has been emphasized by several studies. Although little is known about the exact underlying mechanism of salinomycin, one proposed mechanistic explanation is that Sal increases DNA damage and the levels of DNA damage response proteins 4,35,36 . This effect is in accordance with the finding that salinomycin has a sensitizing effect to enhance cellular apoptosis when used with conventional drugs such as paclitaxel, doxorubicin, and etoposide.…”

“…This combination therapy approach can potentially be applied to the CSC field to improve clinical outcomes by combining CSC-targeted inhibitors with conventional cytotoxic agents to effectively eradicate CSCs and bulk tumor cells at the same time. This added therapeutic effect, combining free salinomycin with other chemotherapeutics, has been demonstrated in vitro [35][36][37] . More recently, some studies reported that, in vitro, treatment with a mixture of anticancer agent-formulated liposomes and CSC inhibitor-formulated polymeric micelles induced a significantly higher anticancer effect than individual administration of singledrug formulated nanoparticles, confirming the intriguing potential of CSC targeted combination therapy to out perform monotherapy 3,4,37 However, the in vivo anti-tumor effect of a mixture of single drug-formulated nanoparticles failed to show significantly greater effects than single nanoparticle drug treatment or free drug combinations 3,4 .…”

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

“…Cell suspension was aliquoted and stored at 280˚C until further use. Tumor cell lysates were used as a source of hTERT protein at 10 7 cell equivalents/ml and loaded on DC with at a 2:1 ratio (DC:tumor cell equivalent) for 12 h. hTERT-positive cell lines used to prepare hTERT pos lysates were FaDu and A375 (6,18,19). hTERT-negative cell line used to prepare hTERT neg lysates was U-2OS (20).…”