Salinomycin in cancer: A new mission for an old agent

Naujokat, Cord; Fuchs, Dominik; Opelz, Gerhard

doi:10.3892/mmr_00000296

Cited by 83 publications

(71 citation statements)

References 36 publications

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“…This compound is now considered an important anticancer drug candidate (17,18). It has recently been reported that salinomycin can selectively kill human breast cancer stem cells, and is 100-fold more effective at reducing the proportion of CSCs than paclitaxel, albeit by an unknown mechanism (19).…”

Section: Introductionmentioning

confidence: 99%

Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells

Zhang

Tian

Song³

et al. 2015

Oncology Reports

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Abstract. Salinomycin is a monocarboxylic polyether antibiotic that has been reported to induce apoptosis in various types of cancer cells with specificity for cancer stem cells. However, its anticancer effect in colorectal cancer stem cells has never been reported. In the present study, we examined the ability of salinomycin to induce cell death in the colorectal cancer stem cell line CD44 + EpCAM + HCT-116, and we measured its in vivo tumor inhibition capacity. Salinomycin dose-dependently induced cytotoxicity in the CD44 + EpCAM + HCT-116 cells and inhibited colony formation. Salinomycin treatment was shown to induce apoptosis, as evidenced by nuclear fragmentation, an increase in the proportion of acridine orange/ethidium bromide-positive cells and an increase in the percentage of Annexin V-positive cells. Apoptosis was induced in colorectal cancer stem cells in a caspase-dependent manner, as shown by an increase in the levels of cleaved caspase-3, -8 and -9. JC-1 staining further revealed that salinomycin induced colorectal cancer cell apoptosis via the mitochondrial pathway. In addition, salinomycin treatment of xenograft mice inhibited the growth of tumors derived from the CD44 + EpCAM + HCT-116 cells. The present study demonstrated that the antibiotic salinomycin exerts an anti-colorectal cancer effect in vitro and in vivo, suggesting salinomycin as a potential drug for colorectal cancer therapy. IntroductionColorectal cancer (CRC) is the third most common malignancy worldwide, accounting for ~10% of all cancer cases and CRC is one of the most common causes of death related to gastrointestinal cancers (1-3). Although the incidence rates of colon cancer have declined somewhat, current therapies are associated with serious side-effects, high cost and recurrence rates exceeding 50%, primarily due to the development of acquired chemoresistance to conventional chemotherapeutics (4,5).Emerging data suggest that malignant tumors contain a small distinct population of cancer stem cells (CSCs), which are responsible for tumor initiation and propagation (6). Stem cell research and the cancer stem cell (CSC) hypothesis have shown that colonic stem cells or CSCs are involved in tissue regeneration and colonic carcinogenesis (7-9). Drug-resistant CSCs are thought to be one of the key causes of CRC treatment failure, and it is hypothesized that these cells are ultimately the likely cause of metastasis and tumor recurrence (10-12). Most modern treatments are ineffective against solid tumors and this may be the result of the increased resistance of CSCs (13). Therefore, it is vital to find novel therapeutic methods to eradicate CSCs and enable the development of more effective treatment protocols (14).Salinomycin is a 751-Da monocarboxylic polyether antibiotic, which was initially used to eliminate bacteria, fungi and parasites and is fed to ruminants to improve nutrient absorption and feeding efficiency (15,16). This compound is now considered an important anticancer drug candidate (17,18). It has recently been reporte...

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Section: Introductionmentioning

confidence: 99%

Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells

Zhang

Tian

Song³

et al. 2015

Oncology Reports

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“…Salinomycin-induced apoptosis in human cancer cells is mediated by an uncommon pathway and independent of typical mechanism like activated caspases, death receptors like the CD95/DC95 ligand system or tumor suppressor protein p53 [15,19]. Demonstrating that Salinomycin-induced apoptosis in human CC cells is independent of caspase-3 activation confirms that apoptosis is mediated through an uncommon pathway.…”

Section: Discussionmentioning

confidence: 49%

“…However, the exact mechanisms by which Salinomycin induces apoptosis are still incomplete understood [15]. Salinomycin-induced apoptosis in human cancer cells is mediated by an uncommon pathway and independent of typical mechanism like activated caspases, death receptors like the CD95/DC95 ligand system or tumor suppressor protein p53 [15,19].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of Salinomycin on human cholangiocarcinoma: induction of apoptosis and impairment of tumor cell proliferation in vitro

Lieke¹,

Ramackers²,

Bergmann³

et al. 2013

Z Gastroenterol

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Background: Cholangiocarcinoma (CC) is a primary liver cancer with increasing incidence worldwide. Despite all efforts made in past years, prognosis remains to be poor. At least in part, this might be explained by a pronounced resistance of CC cells to undergo apoptosis. Thus, new therapeutic strategies are imperatively required. In this study we investigated the effect of Salinomycin, a polyether ionophore antibiotic, on CC cells as an appropriate agent to treat CC. Salinomycin was quite recently identified to induce apoptosis in cancer stem cells and to overcome apoptosis-resistance in several leukemia-cells and other cancer cell lines of different origin. Methods: To delineate the effects of Salinomycin on CC, we established an in vitro cell culture model using three different human CC cell lines. After treatment apoptosis as well as migration and proliferation behavior was assessed and additional cell cycle analyses were performed by flowcytometry.

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“…Salinomycin is a polyether ionophore that was originally used as an antibiotic to prevent infectious diseases in poultries (12). Recently, cytotoxic effects of this drug on human neoplastic cells have been demonstrated in various types of cancer (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

The impact of metformin and salinomycin on transforming growth factor β-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cell lines

et al. 2016

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Abstract. The epithelial-to-mesenchymal transition (EMT) is highly involved in the development of metastases. EMT transforms epithelial carcinoma cells into mesenchymal-like cells, characterized by increased cell migration and invasiveness. Transforming growth factor β (TGFβ) appears to be crucial in this process. Metformin and salinomycin have demonstrated an EMT inhibitory effect. The current experiments indicate that these substances specifically inhibit TGFβ-induced EMT in non-small cell lung cancer (NSCLC) cell lines. The NSCLC cell lines A549 and HCC4006 were stimulated with TGFβ for 48 h to induce EMT. Metformin or salinomycin was added simultaneously with TGFβ to inhibit TGFβ-induced EMT. Western blot analyses of E-cadherin and vimentin were performed to detect changes in EMT marker expression, and a wound healing assay was conducted to determine the potential effects on cell migration. The effects of the two drugs on cell viability were also investigated using MTS tetrazolium dye assays. The results revealed that cells undergoing EMT by application of TGFβ exhibited a downregulation of E-cadherin and an upregulation of vimentin protein expression on western blot analyses, and an increased capacity for cell migration. Simultaneous application of TGFβ and metformin specifically inhibited EMT and increased E-cadherin expression. At the higher dose tested, salinomycin also inhibited EMT, despite an increase in vimentin expression in the two cell lines. Furthermore, metformin and salinomycin, at the two concentrations tested, inhibited cell migration. These findings demonstrate that metformin and salinomycin are able to block EMT and inhibit EMT-induced cell migration. Thus, these two substances are novel EMT inhibiting drugs that have the potential to specifically control EMT and metastatic spread in NSCLC.

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Salinomycin in cancer: A new mission for an old agent

Cited by 83 publications

References 36 publications

Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells

Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells

Impact of Salinomycin on human cholangiocarcinoma: induction of apoptosis and impairment of tumor cell proliferation in vitro

The impact of metformin and salinomycin on transforming growth factor β-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cell lines

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