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

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• 作者：Vaibhav Jadhav^a ; ^{vaibhav.jadhav@nmims.edu.in" class="auth_mail" title="E-mail the corresponding author} ; Pritha Ray^b ; ^{pray@actrec.gov.in" class="auth_mail" title="E-mail the corresponding author} ; Geetanjali Sachdeva^c ; ^{sachdevag@nirrh.res.in" class="auth_mail" title="E-mail the corresponding author} ; Purvi Bhatt^a ; ^{purvi.bhatt@nmims.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Arsenic trioxide ; Nanoparticles ; Prostate cancer ; p21WAF1/CIP1 ; Cell cycle arrest ; Epigenetic modulations
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：148
• 期：Complete
• 页码：41-52
• 全文大小：1922 K

文摘

Arsenic trioxide (As₂O₃) 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 As₂O₃ nanoparticles was determined on human prostate cancer cell lines.

<h4 id="absSec_2">Main methodsh4>

In vitro anticancer efficacy of biopolymer coated As₂O₃ 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 As₂O₃ NPs.

<h4 id="absSec_3">Key findingsh4>

Our results demonstrate that the nanoparticulate formulation of dimercaptosuccinic acid (DMSA) and chitosan coated As₂O₃ 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.

<h4 id="absSec_4">Significanceh4>

Biopolymer coated As₂O₃ nanoparticles induced reversal of mono, di and tri-methylation of histone H3 at lysine 9 residue. Acetylation of histone H3 at lysine 14 residue and phosphorylation of H3 at serine 10 residue synergistically activated p21^WAF1/CIP1 gene thereby leading to apoptosis in the LNCaP and PC-3 cells. Treatment with As₂O₃ nanoparticles arrested the cells in G0-G1 and G2-M phase of cell cycle in LNCaP and PC-3 cells respectively. Thus, biocompatible As₂O₃ nanoparticles with reduced toxicity to normal cells but the antiproliferative effect on prostate cancer cell lines follow similar death pathway as that of bare As₂O₃ nanoparticles.