Nimbolide-based nanomedicine inhibits breast cancer stem-like cells by epigenetic reprogramming of DNMTs-SFRP1-Wnt/β-catenin signaling axis.

Autor:	Mohapatra P; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.; Regional Centre for Biotechnology, Faridabad 121001, Haryana, India., Madhulika S; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.; Regional Centre for Biotechnology, Faridabad 121001, Haryana, India., Behera S; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India., Singh P; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.; Regional Centre for Biotechnology, Faridabad 121001, Haryana, India., Sa P; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.; Regional Centre for Biotechnology, Faridabad 121001, Haryana, India., Prasad P; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India., Swain RK; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India., Sahoo SK; Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Sep 09; Vol. 34, pp. 102031. Date of Electronic Publication: 2023 Sep 09 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.102031
Abstrakt:	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. Competing Interests: Authors declare no competing interests. (© 2023 The Authors.)
Databáze:	MEDLINE
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