DNA damage and p53-mediated growth arrest in human cells treated with platinum nanoparticles.
OBJECTIVE
Platinum-based therapeutic agents are widely used in medicine. Thus, a thorough understanding of their mechanism of action in cells is warranted. This study investigates the uptake and bioactivity (e.g., cytotoxicity, genotoxicity and protein expression) of platinum nanoparticles (Pt-NPs, approximately 5-8 nm in size) in human cells.


METHODS
Pt-NPs capped with polyvinyl alcohol were synthesized, characterized and incubated with human cells. Uptake and the biological properties were evaluated through metabolic activity, genome integrity, cell cycle and protein expression.


RESULTS
Pt-NPs entered the cells through diffusion, and localized inside the cytoplasm. Exposure to the Pt-NP increased DNA damage, accumulation of cells at the S-phase of the cell cycle and apoptosis. A significant number of cells recovered from the stress and formed colonies. Protein-expression levels uncovered upregulation of p53, phosphorylated p53, p21 and downregulation of proliferating cell nuclear antigen following Pt-NP treatment. Pro-caspase 3 and poly-ADP ribose polymerase and cyclin B levels were not altered in both the cell types after Pt-NP exposure.


CONCLUSIONS
The results suggest p53 activation in Pt-NP-treated cells due to genotoxic stress, with subsequent activation of p21 leading to a proliferating cell nuclear antigen-mediated growth arrest and apoptosis. This study recommends development of Pt-NP-based anticancer agents by appropriate surface modifications to augment its innate anticancer activity.
Asharani
P V
PV
Department of Chemistry, Faculty of Science, 3 Science Drive 3, National University of Singapore, Singapore. phsmph@nus.edu.sg
Xinyi
Ng
N
Hande
M Prakash
MP
Valiyaveettil
Suresh
S
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010984:Platinum / Q000008:administration & dosage* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D010984:Platinum