DNA Damage and P53-Mediated Growth Arrest in Human Cells Treated with Platinum Nanoparticles

Abstract

Aim: 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, ∼5–8 nm in size) in human cells. Materials & 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. Conclusion: 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.

Keywords::

• anticancer
• apoptosis
• biodistribution
• cell cycle
• cytotoxicity
• DNA damage
• genotoxicity
• nanomedicine
• nanoparticles
• platinum

supplementary-material

Financial & competing interests disclosure

This study was supported by funding support from NUSNNI, Office of Life Sciences, Academic Research Fund, Ministry of Education, Singapore (T206B3108; WBS: 185-000-153-112). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgments

The authors thank Khaw Aik Kia for his help with the graphics. We thank Departments of Chemistry and Physiology for providing the research facilities.

Additional information

Funding

This study was supported by funding support from NUSNNI, Office of Life Sciences, Academic Research Fund, Ministry of Education, Singapore (T206B3108; WBS: 185-000-153-112). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.