Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity

Schenk, Miriam; Aykut, B.; Teske, Christian; Giese, Nathalia A.; Weitz, Juergen; Welsch, Thilo

doi:10.1016/j.canlet.2014.12.037

Cited by 57 publications

(37 citation statements)

References 37 publications

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“…Given that CRC liver metastasis are the leading cause for CRC-related death [4] this observation promises an important clinical impact. The effectiveness of Sal in vivo has been described before predominantly in subcutaneous tumor models [1, 7, 17, 26, 29–31]. Our data demonstrate the effectiveness of Sal in clinical relevant CRC models for the first time in a convincing extent.…”

Section: Discussionsupporting

confidence: 77%

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Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

et al. 2016

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BackgroundThe polyether antibiotic Salinomycin (Sal) is regarded as an inhibitor of cancer stem cells. Its effectiveness on human colorectal cancer (CRC) cells in vitro has been demonstrated before. The aim of this study was to establish a murine model to investigate the effectiveness of Sal in vivo. Furthermore, we investigated the impact of Sal on Wnt/β-catenin signaling in human CD133+ CRC cells.MethodsThe two murine CRC cell lines MC38 and CT26 were used to analyze the impact of Sal on tumor cell proliferation, viability, migration, cell cycle progression and cell death in vitro. For in vivo studies, CT26 cells were injected into syngeneic BALB/c mice to initiate (i) subcutaneous, (ii) orthotopic, or (iii) metastatic CRC growth. Sal was administered daily, 5-Fluoruracil served as a control. For mechanistic studies, the CD133+and CD133- subpopulations of human CRC cells were separated by flow cytometry and separately exposed to increasing concentrations of Sal. The impact on Wnt/β-catenin signaling was determined by Western blotting and quantitative PCR.ResultsSal markedly impaired tumor cell viability, proliferation and migration, and induced necrotic cell death in vitro. CRC growth in vivo was likewise inhibited upon Sal treatment. Interference with Wnt signaling and reduced expression of the Wnt target genes Fibronectin and Lgr5 indicates a novel molecular mechanism, mediating anti-tumoral effects of Sal in CRC.ConclusionSal effectively impairs CRC growth in vivo. Furthermore, Sal acts as an inhibitor of Wnt/β-catenin signaling. Thus, Salinomycin represents a promising candidate for clinical CRC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2879-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

“…Sal was dissolved in dimethyl sulfoxide (DMSO) for in vitro analysis [16] or in corn oil for in vivo applications [17]. 5-FU was dissolved in phosphate buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

et al. 2016

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“…Another approach is to perform high-throughput chemical screen to identify compounds that could induce cell death in CSCs generated by EMT. The ionophore salinomycin was identified as a potential CSC targeting agent that subsequently blocked tumor formation and metastasis in vivo in different malignancies [103, 104]. Recent studies have revealed that salinomycin was found to exert synergistic cytotoxicity in combination with chemotherapy drugs such as doxorubicin and fluorouracil (5-FU) in HCC cells.…”

Section: Therapies Targeting Csc and Emt Phenotypesmentioning

confidence: 99%

Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

2016

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Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide despite the development of various therapeutic strategies. A better understanding of the mechanisms responsible for HCC initiation and progression is essential for the development of more effective therapies. The cancer stem cell (CSC) model has provided new insights into the development and progression of HCC. CSCs are specialized tumor cells that are capable of self-renewal and have long-term repopulation potential. As they are important mediators of tumor proliferation, invasion, metastasis, therapy resistance, and cancer relapse, the selective targeting of this crucial population of cells has the potential to improve HCC patient outcomes and survival. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC has gained increasing attention. This multi-step reprograming process resulting in a phenotype switch from an epithelial to a mesenchymal cellular state has been closely associated with the acquisition of stem cell-like attributes in tumors. Moreover, CSC mediates tumor metastasis by maintaining plasticity to transition between epithelial or mesenchymal states. Therefore, understanding the molecular mechanisms of the reprograming switches that determine the progression through EMT and generation of CSC is essential for developing clinically relevant drug targets. This review provides an overview of the proposed roles of CSC in HCC and discusses recent results supporting the emerging role of EMT in facilitating hepatic CSC plasticity. In particular, we discuss how these important new insights may facilitate rational development of combining CSC- and EMT-targeted therapies in the future.

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“…Another important effect on cancer is that salinomycin is able to reduce metastasis formation [17–19] and inhibits EMT by activation of FOXO3a [20]. Salinomycin was also utilized as additive in several other combinational treatment approaches overcoming acquired drug resistance [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases

et al. 2016

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Luminal A breast cancer is the most common breast cancer subtype which is usually treated with selective estrogen receptor modulators (SERMS) like tamoxifen. Nevertheless, one third of estrogen receptor positive breast cancer patients initially do not respond to endocrine therapy and about 40% of luminal A breast tumors recur in five years. In this study, we investigated an alternative treatment approach by combining tamoxifen and salinomycin in luminal A breast cancer cell lines. We have found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα. Thereby salinomycin increases the intracellular calcium level. This leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members. Since this process is essential for luminal A breast cancer cells to circumvent tamoxifen treatment, the combination of both drugs induces cytotoxicity in tamoxifen sensitive as well as resistant luminal A breast cancer cell lines.

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Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity

Cited by 57 publications

References 37 publications

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases

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