Salinomycin-Loaded High-Density Lipoprotein Exerts Promising Anti-Ovarian Cancer Effects by Inhibiting Epithelial–Mesenchymal Transition

Abstract

Background Effective treatments for ovarian cancer remain elusive, and survival rates have long been considered grim. Ovarian cancer stem cells (OCSCs) and epithelial–mesenchymal transition (EMT) are associated with cancer progression and metastasis, as well as drug resistance and eventual treatment failure. Salinomycin (Sal) has an extensive effect on a variety of cancer stem cells (CSCs); however, its poor water solubility and toxicity to healthy tissues at high doses limit further research into its potential as an anti-cancer drug. We proposed a therapeutic strategy by constructing a tumor-targeting carrier that mimics high-density lipoprotein (HDL) to synthesize salinomycin-loaded high-density lipoprotein (S-HDL). This strategy helps reduce the side effects of salinomycin, thereby improving its clinical benefits. Methods OCSCs were isolated from ovarian cancer cells (OCCs) and the uptake of HDL nanoparticles was observed using laser confocal microscopes. After the cell viability analysis revealed the inhibitory effect of S-HDL on OCCs and OCSCs, the main biological processes influenced by S-HDL were predicted with a transcriptome sequencing analysis and verified in vitro and in vivo. Results Cellular uptake analysis showed that the HDL delivery system was able to significantly enhance the uptake of Sal by OCCs, tentatively validating the targeting role of recombinant HDL, so that S-HDL could reduce the toxicity of Sal and increase its anti-ovarian cancer effects. Conversely, S-HDL could exert anti-ovarian cancer effects by inhibiting the proliferation of OCCs and OCSCs, promoting apoptosis, blocking EMT, and suppressing stemness and angiogenesis-related protein expression in vitro and in vivo. Conclusion S-HDL had stronger anti-ovarian cancer effects than unencapsulated Sal. Thus, it may be a potential agent for ovarian cancer treatment in the future.

Selected markers of ovarian cancer and their relation to targeted therapy (Review)

“…Constructing a carrier mimicking high-density lipoprotein (HDL) in combination with salinomycin (S-HDL) has been demonstrated to have potent anticancer effects in OC as it inhibits translation of the CSCs proteins c-Myc, NANOG, OCT4 and SOX2 which are associated with chemoresistance and OC recurrence ( 34 ). The authors of the investigation on the effects of metformin and salinomycin consider that these two drugs will be an effective future therapy in improving survival and preventing recurrence of OC.…”

“…Salinomycin, an ionophore antibiotic isolated from Streptomyces albus, selectively eradicates CSCs (32)(33)(34). Previous studies on OC cell lines (OVCAR3) have revealed an inhibitory effect of salinomycin in combination with paclitaxel on CD44(+) and CD117(+) expression (32).…”

Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches

“…Salinomycin has also been shown to be a selective inhibitor of BCSC and OCSC. It induces apoptosis in OCSC and selectively kills BCSC while reducing tumor growth and EMT [ 416 , 417 , 458 ]. However, its disadvantage is poor solubility in water and poor bioavailability, which can be remedied by conjugation with CD133-targeted nanoparticles [ 459 ].…”

“…OC cell line (CD133+ population), normal ovarian epithelial line, xenografts Downregulation of stemness markers (MYCN, NANOG, OCT4, SOX2) in vitro and in vivo, induction of apoptosis [417].…”

A Concise Review of Prodigious Salinomycin and Its Derivatives Effective in Treatment of Breast Cancer: (2012–2022)

“…SAL has the ability to promote differentiation of cancer cells early on in development, and it can reprogram epithelial growth that undergoes epithelial mesenchymal transition (EMT) and leads to the upregulation and expression of certain genes, such as mammary epithelial differentiation [42,64]. Based on these findings, SAL can eliminate CSCs through multiple mechanisms of action known from the literature (Table 1).…”