Biocompatible arsenic trioxide nanoparticles induce cell cycle arrest by p21(WAF1/CIP1) expression via epigenetic remodeling in LNCaP and PC3 cell lines.

Abstract Aims Arsenic trioxide (As 2 O 3 ) is a well-known anticancer drug and is approved by the FDA for its use in acute promyelocytic leukemia. In this study, anticancer and antiproliferative mechanism of biocompatible As 2 O 3 nanoparticles was determined on human prostate cancer cell lines. Main methods In vitro anticancer efficacy of biopolymer coated As 2 O 3 NPs was investigated in LNCaP and PC-3 cell lines, by assessing DNA damage, changes in epigenetic modulations, expression level of apoptotic markers and cell cycle analysis following treatment with As 2 O 3 NPs. Key findings Our results demonstrate that the nanoparticulate formulation of dimercaptosuccinic acid (DMSA) and chitosan coated As 2 O 3 is capable of inducing morphological changes, DNA damage and caspase-dependent apoptosis along with the expression of cyclin-dependent kinase inhibitor p21 by upregulation of Bax and downregulation of Bcl-2 and Bcl-xL proteins. The expression of cyclin-dependent kinase inhibitor – p21 was found to be triggered by changes in epigenetic modifications at histone tails. Significance Biopolymer coated As 2 O 3 nanoparticles induced reversal of mono, di and tri-methylation of histone H 3 at lysine 9 residue. Acetylation of histone H 3 at lysine 14 residue and phosphorylation of H 3 at serine 10 residue synergistically activated p21 WAF1/CIP1 gene thereby leading to apoptosis in the LNCaP and PC-3 cells. Treatment with As 2 O 3 nanoparticles arrested the cells in G0-G1 and G2-M phase of cell cycle in LNCaP and PC-3 cells respectively. Thus, biocompatible As 2 O 3 nanoparticles with reduced toxicity to normal cells but the antiproliferative effect on prostate cancer cell lines follow similar death pathway as that of bare As 2 O 3 nanoparticles.