Nanoparticle-Encapsulated Camptothecin: Epigenetic Modulation in DNA Repair Mechanisms in Colon Cancer Cells.

Aisha Farhana,Jia Bei Tong,Suresh Kumar Subbiah,Abdullah Alsrhani,Pooi Ling Mok,Avin Ee-Hwan Koh

doi:10.3390/molecules26175414

Aisha Farhana, Jia Bei Tong + Show 4 more

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https://doi.org/10.3390/molecules26175414

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Abstract

Molecular crosstalk between the cellular epigenome and genome converge as a synergistic driver of oncogenic transformations. Besides other pathways, epigenetic regulatory circuits exert their effect towards cancer progression through the induction of DNA repair deficiencies. We explored this mechanism using a camptothecin encapsulated in β-cyclodextrin–EDTA–Fe3O4 nanoparticles (CPT-CEF)-treated HT29 cells model. We previously demonstrated that CPT-CEF treatment of HT29 cells effectively induces apoptosis and cell cycle arrest, stalling cancer progression. A comparative transcriptome analysis of CPT-CEF-treated versus untreated HT29 cells indicated that genes controlling mismatch repair, base excision repair, and homologues recombination were downregulated in these cancer cells. Our study demonstrated that treatment with CPT-CEF alleviated this repression. We observed that CPT-CEF exerts its effect by possibly affecting the DNA repair mechanism through epigenetic modulation involving genes of HMGB1, APEX1, and POLE3. Hence, we propose that CPT-CEF could be a DNA repair modulator that harnesses the cell’s epigenomic plasticity to amend DNA repair deficiencies in cancer cells.

Highlights

Epigenetic mechanisms are essential for the ontogenesis of mammals and the maintenance of tissue-specific gene expression [1,2]
Our results reveal three important genes, High mobility group box 1 (HMGB1), APEX1, and POLE3, that function in the epigenetic control of a DNA-repair mechanism, which modulates cancer in HT29 cells, and induce apoptosis
In the context of epigenetic study of cancer cell development, the analysis indicated that treatment with camptothecin encapsulated in β-cyclodextrin–EDTA–Fe3O4 nanoparticles (CPT-CEF) could reverse these deficiencies by modulating the expression of these genes

Summary

Introduction

Epigenetic mechanisms are essential for the ontogenesis of mammals and the maintenance of tissue-specific gene expression [1,2]. The two common types present in tumors are demethylation and de novo methylation of CpG islands [10]. These result in expression profiles that promote tumor growth. The deregulation of this process affects the maintenance of repressive chromatin, thereby causing an aberrant promotion of gene expression [11]. This characteristic makes epigenetic modifications a perfect target for therapeutic intervention for cancer [12]

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