Salinomycin is an antibacterial and coccidiostat ionophore therapeutic drug. Salinomycin has been shown by Piyush Gupta et al. of the Massachusetts Institute of Technology and the Broad Institute to kill breast cancer stem cells in mice at least 100 times more effectively than the anti-cancer drug paclitaxel. The mechanism of action by which salinomycin kills cancer stem cells specifically remains unknown, but is thought to be due to its action as a potassium ionophore. Salinomycin could induce apoptosis of human cancer cells. Promising results from a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers.
Chemical Formula: C42H69NaO11
Exact Mass: 750.49181
Molecular Weight: 772.98
Elemental Analysis: C, 67.17; H, 9.39; O, 23.43
Salinomycin is a potent inhibitor of the Wnt signaling cascade. Incubation of the malignant lymphocytes with Salinomycin induces apoptosis within 48 h, with a mean IC50 of 230 nM. Salinomycin is also an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor.
Salinomycin is a novel and an effective anticancer drug, inhibits SW620 cells and Cisp-resistant SW620 cells with IC50 of 1.54±0.23 μM and 0.32±0.05 μM, respectively. Salinomycin is found to have the ability to kill both cancer stem cells (CSCs) and therapy-resistant cancer cells. After continuous Salinomycin treatment for 48 h, the apoptotic cells are observed under the microscope and counted randomly at least 100 cells in one field. The number of apoptotic cells which are stained by Hoechst33342 is significantly increased in Cisp-resistant SW620 cells (20.20±3.72) than that of SW620 cells (9.40±2.07) per 100 cells (p<0.05). After treatment with Salinomycin for 48 h, flow cytometric analysis is used to detect the cell apoptosis both in SW620 cells and Cisp-resistant SW620 cells. The cell apoptotic rate in Cisp-resistant SW620 cells (37.82±3.63%) is significantly higher than that of SW620 cells (16.78±2.56%) (p<0.05).
After administration of 4 mg/kg Salinomycin (Sal), 8 mg/kg Salinomycin and 10 uL/g saline water for 6 weeks, the mice are sacrificed. The size of the liver tumors in the Salinomycin treatment groups diminishes compare with the control group. The mean diameter of the tumors decreases from 12.17 mm to 3.67 mm (p<0.05) and the mean volume (V=length×width2×0.5) of the tumors decreases from 819 mm3 to 25.25 mm3 (p<0.05). Next, the tumors are harvested, followed by HE staining, immunohistochemistry, and TUNEL assays, to assess the anti-tumor activity of Salinomycin. HE staining shows that the structure of the liver cancer tissue:nuclei of different sizes, hepatic cord structure is destroyed. Immunohistochemistry shows that PCNA expression is lower after Salinomycin treatment. HE staining and TUNEL assays indicates the Salinomycin-treated groups has higher apoptosis rates than control. Furthermore, immunohistochemistry shows an increased Bax/Bcl-2 ratio after Salinomycin treatment. The protein expression of β-catenin decreases in the Salinomycin treatment groups compared with control.
Salinomycin is a kind of monocarboxylic acid polyether type antibiotics, produced by the fermentation of Streptomyces albus, possesses a specific cyclic structure, and can form a complex compound with the pathogenic microorganisms and the extracellular cations of coccidian, especially K+, Na+, Rb+, to alter the intracellular and extracellular ion concentrations.
Zhao P, Dong S, Bhattacharyya J, Chen M. iTEP Nanoparticle-Delivered Salinomycin Displays an Enhanced Toxicity to Cancer Stem Cells in Orthotopic Breast Tumors. Mol Pharm. 2014 Aug 4;11(8):2703-12. doi: 10.1021/mp5002312. Epub 2014 Jul 1. PubMed PMID: 24960465.
Lu W, Li Y. Salinomycin suppresses LRP6 expression and inhibits both Wnt/β-catenin and mTORC1 signaling in breast and prostate cancer cells. J Cell Biochem. 2014 Jun 6. doi: 10.1002/jcb.24850. [Epub ahead of print] PubMed PMID: 24905570.
Huang X, BorgstrÃ¶m B, MÃ¥nsson L, Persson L, Oredsson S, Hegardt C, Strand D. Semisynthesis of SY-1 for Investigation of Breast Cancer Stem Cell Selectivity of C-Ring-Modified Salinomycin Analogues. ACS Chem Biol. 2014 Jul 18;9(7):1587-94. doi: 10.1021/cb5002153. Epub 2014 May 29. PubMed PMID: 24841425.
Klose J, Stankov MV, Kleine M, Ramackers W, Panayotova-Dimitrova D, JÃ¤ger MD, Klempnauer J, Winkler M, Bektas H, Behrens GM, Vondran FW. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. PLoS One. 2014 May 9;9(5):e95970. doi: 10.1371/journal.pone.0095970. eCollection 2014. PubMed PMID: 24816744; PubMed Central PMCID: PMC4015957.
Boehmerle W, Muenzfeld H, Springer A, Huehnchen P, Endres M. Specific targeting of neurotoxic side effects and pharmacological profile of the novel cancer stem cell drug salinomycin in mice. J Mol Med (Berl). 2014 Aug;92(8):889-900. doi: 10.1007/s00109-014-1155-0. Epub 2014 Apr 27. PubMed PMID: 24770997.
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