title: Biocompatible arsenic trioxide nanoparticles induce cell cycle arrest by p21(WAF1/CIP1) expression via epigenetic remodeling in LNCaP and PC3 cell lines.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS University, Vile Parle (West), Mumbai 400056, India. Electronic address: vaibhav.jadhav@nmims.edu.in.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Jadhav
authors.affiliation: Ray Lab, Khanolkar Shodhika, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India. Electronic address: pray@actrec.gov.in.
authors.forename: Pritha
authors.initials: P
authors.lastname: Ray
authors.affiliation: Primate Biology Department, National Institute for Research in Reproductive Health (NIRRH), Parel, Mumbai 400012, India. Electronic address: sachdevag@nirrh.res.in.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Sachdeva
authors.affiliation: Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS University, Vile Parle (West), Mumbai 400056, India. Electronic address: purvi.bhatt@nmims.edu.
authors.forename: Purvi
authors.initials: P
authors.lastname: Bhatt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles / Q000627:therapeutic use; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D001672:Biocompatible Materials; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010087:Oxides; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Cell cycle arrest; Epigenetic modulations; Nanoparticles; Prostate cancer; p21(WAF1/CIP1)