Salinomycin reduces stemness and induces apoptosis on human ovarian cancer stem cell

Abstract

ObjectiveCancer stem cells (CSCs) represent a subpopulation of undifferentiated tumorigenic cells thought to be responsible for tumor initiation, maintenance, drug resistance, and metastasis. The role of CSCs in drug resistance and relapse of cancers could significantly affect outcomes of ovarian cancer patient. Therefore, therapies that target CSCs could be a promising approach for ovarian cancer treatment. The antibiotic salinomycin has recently been shown to deplete CSCs. In this study, we evaluated the effect of salinomycin on ovarian cancer stem cells (OCSCs), both alone and in combination with paclitaxel (PTX).MethodsThe CD44+CD117+CSCs were obtained from the ascitic fluid of patients with epithelial ovarian cancer by using an immune magnetic-activated cell sorting system. OCSCs were treated with PTX and salinomycin either singly or in combination. Cell viability and apoptosis assays were performed and spheroid-forming ability was measured. The expression of sex determining region Y-box 2 (SOX2) and octamer-binding transcription factor 3/4 (OCT3/4) mRNA was determined using reverse transcription polymerase chain reaction, and protein expression was observed using western blot analysis.ResultsTreatment with salinomycin alone reduced the stemness marker expression and spheroid-forming ability of OCSCs. Treatment with PTX alone did not decrease the viability of OCSCs. Treatment with a combination of salinomycin decreased the viability of OCSCs and promoted cell apoptosis. The enhancement of combination treatment was achieved through the apoptosis as determined by annexin V/propidium iodide (PI) staining, caspase-3 activity, and DNA fragmentation assay.ConclusionBased on our findings, combining salinomycin with other anti-cancer therapeutic agents holds promise as an ovarian cancer treatment approach that can target OCSCs.

Ionophores: Potential Use as Anticancer Drugs and Chemosensitizers

“…SAL came in forefront as a potential anticancer drug in 2009 when Gupta et al screened roughly 16,000 compounds for their selective anticancer efficacy against CSCs and found SAL at least 100-fold more effective than paclitaxel, a commonly used anticancer drug [ 7 ]. Following this work, several other studies pointed towards SAL’s selectivity in targeting cancer stem cells practically in every type of cancer [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ] as well as other multidrug resistance (MDR) cancer cells [ 81 , 82 ]. Although the exact mechanism by which SAL targets cancers is not known, it is very clear that it influences multiple pathways to impart its effects.…”

Transcription factor Six2 induces a stem cell‐like phenotype in renal cell carcinoma cells

“…A previous study showed that salinomycin exhibits a specific killing capacity on CSCs by sequestering iron in lysosomes [20]. In addition, salinomycin could suppress the stemness and induce the apoptosis on human ovarian CSCs [21]. Notably, salinomycin reduces the stemness and epithelial-mesenchymal transition process of RCC cells [22].…”

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

“…Until now, there have been only limited data showing the effects of SAL and its derivatives on OvCa cells. The recent data indicated that SAL itself affects a wide spectrum of mechanisms against OvCa biology, such as inhibition of the epithelial-mesenchymal transition (EMT) process (responsible for the development of metastatic disease), eradication of the CSC population (CD44 + CD117 + ), and inhibition of the NF-kB signaling pathway (upregulation of proteins related to that pathway correspond with poor clinical prognosis in OvCa) [41][42][43][44]. Our study, for the first time, demonstrates that the combination of SAL with cytostatic agents (5FU and GEM) is more effective than SAL used alone or its amide and ester derivatives.…”