Salinomycin Toxicity Research Articles

Evaluation of The Growth Promoting, Economic Impact and Possible Ameliorative Effect of Hawthorn (Crataegus Spp) against Salinomycin Toxicity in Broiler Chicks

Evaluation of The Growth Promoting, Economic Impact and Possible Ameliorative Effect of Hawthorn (Crataegus Spp) against Salinomycin Toxicity in Broiler Chicks

P06-02 Distinct transcriptomic differences between chicken and turkey in molecular toxicity of salinomycin

P06-02 Distinct transcriptomic differences between chicken and turkey in molecular toxicity of salinomycin

Hepatoprotective and renoprotective effects of silymarin against salinomycin-induced toxicity in adult rabbits

Salinomycin sodium, a licensed coccidiostat in rabbits, is used for fattening at a dose of 20-25 mg/kg. Salinomycin toxicity may arise from many risk factors (e.g., overdosage or use in non-target animal species). Silymarin extracted from milk thistle has antioxidant, anti-inflammatory, and antiviral properties. This study aimed to investigate the adverse impacts of oral administration of salinomycin for 28 consecutive days and how to reduce its risks and side effects by administering silymarin. Eighty-four male New Zealand White bucks (1.750-2.000 kg) were randomly divided into seven groups (12 each). Group one was the control. Groups two and three were administered salinomycin orally (doses of 20 and 40 mg/kg ration). Group four was administered salinomycin (20 mg/kg ration) and silymarin (6.5 mg/kg body weight [BW]). Group five received salinomycin (40 mg/kg ration) and silymarin (13 mg/kg BW). Groups six and seven were administered silymarin at doses of 6.5 and 13 mg/kg BW. Rabbits were euthanized and slaughtered on day 29 using the Halal method. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urea, total proteins, albumin, total cholesterol, and high- and low-density lipoprotein (HDL and LDL) were analyzed in serum. Glutathione (GSH), superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) were estimated in the liver. A histopathological investigation was performed on the liver and kidney. The MDA activity, AST, ALT, total protein, albumin, total cholesterol, triglyceride, LDL, urea, and creatinine values were significantly elevated in groups two and three. The GSH, catalase, SOD, and HDL were significantly lower in these groups than in the control group. There were moderate pathologic changes in the liver and kidney of the third group. However, the results of the fourth and fifth groups improved more than those of the second and third groups. The results of the sixth and seventh groups were nearly the same as those of the control group. Salinomycin toxicity was caused by oxidative damage because of reactive oxygen species formation. Silymarin (6.5 or 13 mg/kg BW) tends to prevent and treat accidental toxicity. However, the high dose of silymarin (13 mg/kg BW) had more renal and hepatoprotective capacities.

Targeting Telomerase Enhances Cytotoxicity of Salinomycin in Cancer Cells.

Salinomycin exhibits significant systemic adverse reactions such as tachycardia and myoglobinuria in mammals, which hinders its application as a drug for human cancers. Although many strategies aimed at increasing salinomycin’s toxicity to cancer cells have been identified to allow a lower dose of salinomycin to be used, they often cause normal cell damage by themselves. Thus, it is urgent to find more effective methods to increase salinomycin’s toxicity to cancer cells with little influences on normal cells. Telomerase, which is expressed highly in most cancer cells rather than normal somatic cells, plays central roles in cancer cell fate regulation. Targeting telomerase represents a potential method for enhancing salinomycin’s cytotoxicity to cancer cells with little effects on normal cells. Herein, we improve the toxicity of salinomycin against cancer cells by telomerase inhibition BIBR1532 (BIBR), which binds to the active site of telomerase reverse transcriptase. We find that a non-toxic dose of BIBR can enhance cytotoxicity of salinomycin in MCF-7 and MDA-MB-231 cells. Moreover, BIBR enhances mammosphere formation inhibition mediated by salinomycin in MCF-7 and MDA-MB-231 cells. Further studies show that BIBR enhances tumor growth inhibition induced by salinomycin in vivo. To our knowledge, this is the first example that targeting telomerase improves anti-cancer effects of salinomycin.

A REVIEW OF ADVANCED NANOTECHNOLOGIES AND DRUG DELIVERY SYSTEMS OF SALINOMYCIN AND THEIR ROLE IN TRIPLE-NEGATIVE BREAST CANCER

Cancer cells spread to other tissues and organs when they divide incorrectly. Breast cancer (BC) is the main cause of cancer-related mortality globally. Some recent studies on cancer stem cells (CSCs), drug resistance, tumor recurrence and metastasis, and the significance of CD44+in targeted treatment for breast cancer are covered. Breast cancer stem cells (BCSCs) and bulk BC cells must be eliminated for the disease to be eliminated. Researchers have shown that Streptomyces Albus-derived monocarboxylic polyether antibiotic salinomycin kills human cancer stem cells (CSCs) and prevents the spread and growth of breast cancer cells. Several drug and apoptosis resistance mechanisms may also trigger apoptosis in breast cancer cells when salinomycin is used in combination with the treatment. Apoptosis-resistant cancer cells and cancer stem cells are both susceptible to the anticancer drug salinomycin. Salinomycin may be able to inhibit CSCs, as well as the source and structure modification of salinomycin analog exhibit potent anticancer activity, the effect of salinomycin on chemotherapeutic-resistant CSCs, and the various mechanisms by which salinomycin inhibits cancer stem cells in this study. Method and delivery technique for salinomycin Nano formulation in triple-negative breast cancer and also contains pharmacokinetics and toxicity of salinomycin. Salinomycin-based drug delivery system is the subject of the patent information. Tumor genesis, development, and invasion are all aided by salinomycin. It's possible to boost the effectiveness of cancer therapy by focusing on cancer stem cells (CSCs).

Primary Human Hepatocytes, but Not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity.

Salinomycin is a polyether antibiotic showing anticancer activity. There are many reports of its toxicity to animals but little is known about the potential adverse effects in humans. The action of the drug may be connected to its metabolism. That is why we investigated the cytotoxicity of salinomycin and pathways of its biotransformation using human primary hepatocytes, human hepatoma cells (HepG2), and the mouse fibroblast cell line (Balb/c 3T3). The cytotoxicity of salinomycin was time-dependent, concentration-dependent, and cell-dependent with primary hepatocytes being the most resistant. Among the studied models, primary hepatocytes were the only ones to efficiently metabolize salinomycin but even they were saturated at higher concentrations. The main route of biotransformation was monooxygenation leading to the formation of monohydroxysalinomycin, dihydroxysalinomycin, and trihydroxysalinomycin. Tiamulin, which is a known inhibitor of CYP450 izoenzymes, synergistically induced cytotoxicity of salinomycin in all cell types, including non-metabolising fibroblasts. Therefore, the pharmacokinetic interaction cannot fully explain tiamulin impact on salinomycin toxicity.

Toxicity of salinomycin and identification of its metabolites in Turkey primary hepatocytes

Toxicity of salinomycin and identification of its metabolites in Turkey primary hepatocytes

Effects of salinomycin and CGP37157 on head and neck squamous cell carcinoma cell lines in vitro.

Surgery, radiation, chemotherapy or a combinations of these are all accepted modalities for the treatment of head and neck squamous cell carcinoma (HNSCC). Despite this, 40‑60% of patients suffering from HNSCC develop loco‑regional failure and/or distant metastases. Salinomycin has been demonstrated to be >100‑fold more effective than paclitaxel at causing cancer stem cell death, therefore, it may offer an important improvement in cancer therapy. However, the toxicity of salinomycin is of concern. A possible solution may be the administration of additive drugs, which reduce the toxicity. By inhibiting the mitochondrial Na+/Ca2+ exchanger using the benzodiazepine derivate, CGP37157 (CGP), a significant reduction in salinomycin neuronal toxicity has been observed. This raises the question of whether CGP also inhibits the tumor toxicity of salinomycin. In the present study, the FaDu and HLaC79 C1 HNSCC cell lines were treated with salinomycin with or without CGP. Comparative viability assessments were performed using microscopy, a fluorescein diacetate assay, an MTT assay, a clonogenic assay and annexin V‑propidium iodide staining. The expression levels of MDR‑1 were monitored using reverse transcription‑quantitative polymerase chain reaction. Salinomycin alone, and in combination with CGP, achieved a significant attenuation of cell viability and increased apoptosis in a dose‑dependent manner. However, the tumor toxicity of salinomycin was not inhibited by CGP. The HLaC79 C1 cells were more sensitive to salinomycin, compared with the FaDu cells, with this sensitivity being due to high expression levels of MDR‑1 by the HLaC79 C1 cells. In conclusion, CGP did not counteract the tumor toxicity of salinomycin in vitro and may be a promising drug in future anticancer therapy. The results of the present study encourages further investigation of the toxicological aspects of salinomycin, particularly in human cells and animal models.

Toxicity of salinomycin and narasin in turkeys

Toxicity of salinomycin and narasin in turkeys

Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells

The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2+, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.

P-Glycoprotein Limits Oral Availability, Brain Penetration, and Toxicity of an Anionic Drug, the Antibiotic Salinomycin

Salinomycin is a polyether organic anion that is extensively used as a coccidiostatic antibiotic in poultry and commonly fed to ruminant animals to improve feed efficiency. However, salinomycin also causes severe toxicity when accidentally fed to animals in high doses. In addition, humans are highly sensitive to salinomycin and severe toxicity has been reported. Multidrug efflux transporters like P-glycoprotein (P-gp), BCRP, and MRP2 are highly expressed in the intestine and can restrict the oral uptake and tissue penetration of xenobiotics. The purpose of this study was to investigate whether the anionic drug salinomycin is a substrate for one or more of these efflux pumps. Salinomycin was actively transported by human MDR1 P-gp expressed in polarized MDCK-II monolayers but not by the known organic anion transporters human MRP2 and murine Bcrp1. Using P-gp-deficient mice, we found a marked increase in plasma salinomycin concentrations after oral administration and decreased plasma clearance after intravenous administration. Furthermore, absence of P-gp resulted in significantly increased brain penetration. P-gp-deficient mice also displayed clearly increased susceptibility to salinomycin toxicity. Thus far, P-gp was thought to affect mainly hydrophobic, positively charged or neutral drugs in vivo. Our data show that P-gp can also be a major determinant of the pharmacokinetic behavior and toxicity of an organic anionic drug. Variation in P-gp activity might thus directly affect the effective exposure to salinomycin and possibly to other anionic drugs and toxin substrates. Individuals with reduced or absent P-gp activity could therefore be more susceptible to salinomycin toxicity.