Cromolyn chitosan nanoparticles reverse the DNA methylation of RASSF1A and p16 genes and mitigate DNMT1 and METTL3 expression in breast cancer cell line and tumor xenograft model in mice.

Autor: Motawi TK; Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: tarek.motawi@pharma.cu.edu.eg., El-Maraghy SA; Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: shohda.elmaraghy@pharma.cu.edu.eg., Sabry D; Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Electronic address: dinasabry@kasralainy.edu.eg., Nady OM; Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: omnia.mohammed@pharma.cu.edu.eg., Senousy MA; Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: mohmoud.ali@pharma.cu.edu.eg.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2022 Sep 25; Vol. 365, pp. 110094. Date of Electronic Publication: 2022 Aug 09.
DOI: 10.1016/j.cbi.2022.110094
Abstrakt: Background: Developing epigenetic drugs for breast cancer (BC) remains a novel therapeutic approach. Cromolyn is a mast cell stabilizer emerging as an anticancer drug; its encapsulation in chitosan nanoparticles (CSNPs) improves its effect and bioavailability. However, its effect on DNA and RNA methylation machineries has not been previously tackled.
Methods: The possible anticancer effect of cromolyn CSNPs and its potential as an epigenetic drug was investigated in vitro using MCF-7 human BC cell line and in vivo using Ehrlich ascites carcinoma-xenograft model in mice symbolizing murine mammary adenocarcinoma. Mice were injected with a single dose of Ehrlich ascites carcinoma cells subcutaneously for the induction of tumor mass, and then randomized into three groups: control, cromolyn CSNPs (equivalent to 5 mg cromolyn/kg, i.p.) and plain CSNPs twice/week for 2 weeks.
Results: Cromolyn CSNPs showed prominent anticancer effect in MCF-7 cells by reducing the cell viability percent and enhancing DNA damage in the comet assay demonstrating its apoptotic actions. Mechanistically, cromolyn CSNPs influenced potential epigenetic processes through mitigating DNA methyltransferase 1 (DNMT1) expression, reversing the hypermethylation pattern of the tumor suppressor RASSF1A and p16 genes and attenuating the expression of the RNA N 6 -methyladenosine writer, methyltransferase-like 3 (METTL3). Cromolyn CSNPs diminished ERK1/2 phosphorylation, a possible arm influencing DNMT1 expression. In vivo, cromolyn CSNPs lessened the tumor volume and halted DNMT1 and METTL3 expression in Ehrlich carcinoma mice.
Conclusions: Cromolyn CSNPs have the premise as an epigenetic drug through inhibiting ERK1/2 phosphorylation/DNMT1/DNA methylation and possibly impacting the RNA methylation machinery via mitigating METTL3 expression.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: