Nimbolide-based nanomedicine inhibits breast cancer stem-like cells by epigenetic reprogramming of DNMTs-SFRP1-Wnt/β-catenin signaling axis.
Priyanka MohapatraSwati MadhulikaSomalisa BeheraPriya SinghPratikshya SaPunit PrasadRajeeb Kumar SwainSanjeeb Kumar SahooPublished in: Molecular therapy. Nucleic acids (2023)
Triple-negative breast cancer (TNBC) harbors a high percentage of breast cancer stem-like cells (BCSCs) that significantly contribute to poor prognosis, metastasis, and relapse of the disease. Thus, targeting BCSCs could be a promising approach to combat TNBC. In this context, we investigated nimbolide (Nim), a limonoid triterpenoid that has potent anticancer properties, but poor pharmacokinetics and low bioavailability limit its therapeutic application. So, to enhance the therapeutic potential of Nim, Nim-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Nim NPs) were formulated and the anticancer stem cell (CSC) effects evaluated in vitro and in vivo . In vitro studies suggested that Nim NPs significantly inhibited several inherent characteristics of BCSCs, such as stemness, self-renewability, chemoresistance, epithelial-to-mesenchymal transition (EMT), and migration in comparison to native Nim. Next, the mechanism behind the anti-CSC effect of Nim was explored. Mechanistically, we found that Nim epigenetically restores tumor suppressor gene secreted frizzled-related protein 1 (SFRP1) expression by downregulating DNA methyltransferases (DNMTs), leading to Wnt/β-catenin signaling inhibition. Further, in vivo results demonstrated that Nim NPs showed enhanced anti-tumor and anti-metastatic effects compared to native Nim in two preclinical models without any systemic toxicity. Overall, these findings provide proof of concept that Nim-based phytonanomedicine can inhibit BCSCs by epigenetic reprogramming of the DNMTs-SFRP1-Wnt/β-catenin signaling axis.
Keyphrases
- poor prognosis
- stem cells
- cell proliferation
- long non coding rna
- squamous cell carcinoma
- dna methylation
- gene expression
- epithelial mesenchymal transition
- oxidative stress
- small cell lung cancer
- mesenchymal stem cells
- signaling pathway
- cell therapy
- cell free
- transcription factor
- long noncoding rna
- atomic force microscopy
- case control
- free survival
- childhood cancer