Mitochondrial dysfunction, autophagy stimulation and non-apoptotic cell death caused by nitric oxide-inducing Pt-coated Au nanoparticle in human lung carcinoma cells

Mohd Javed Akhtar; Maqusood Ahamed; Hisham A Alhadlaq; Sudhir Kumar; Salman A Alrokayan

doi:10.1016/j.bbagen.2019.129452

Mitochondrial dysfunction, autophagy stimulation and non-apoptotic cell death caused by nitric oxide-inducing Pt-coated Au nanoparticle in human lung carcinoma cells

Biochim Biophys Acta Gen Subj. 2020 Jan;1864(1):129452. doi: 10.1016/j.bbagen.2019.129452. Epub 2019 Oct 30.

Authors

Mohd Javed Akhtar¹, Maqusood Ahamed², Hisham A Alhadlaq³, Sudhir Kumar⁴, Salman A Alrokayan⁵

Affiliations

¹ King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: mjakhtar@ksu.edu.sa.
² King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia.
³ Department of Physics and Astronomy, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.
⁴ Department of Zoology, University of Lucknow, Lucknow 226007, UP, India.
⁵ Department of Biochemistry, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.

PMID: 31676295
DOI: 10.1016/j.bbagen.2019.129452

Abstract

Background: Reactive oxygen species (ROS)-mediated cancer therapeutic has been at higher appreciation than those mediated by reactive nitrogen species. Cytotoxic mechanism of a novel nitric oxide (NO) inducing-Pt coated Au nanoparticle (NP) has been comparatively studied with the well-established ROS inducing Pt-based anticancer drug cisplatin in human lung A549 carcinoma cells.

Methods: Cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, thiobarbituric acid substances (TBARS) and C11-Boron dipyrromethene (BODIPY). ROS (O^2·- and H₂O₂) was measured with dihydroethidium (DHE) and H₂O₂-specific sensor. Nitric oxide (NO) and mitochondrial dysfunction were evaluated respectively by NO-specific probe DAR-1 and JC-1. Autophagy was determined by lysotracker (LTR) and monodansylcadaverine (MDC) applied tandemly whereas apoptosis/necrosis by Hoechst/PI and caspase 3 activity.

Results: IC50 (concentration that inhibited cell viability by 50%) of Pt coated Au NP came to be 0.413 μM whereas IC50 of cisplatin came out to 86.5 μM in A549 cells treated for 24 h meaning NPs toxicity was over 200 times higher than cisplatin. However, no significant stimulation of intracellular ROS was observed at the IC50 of Pt coated Au NPs in A549 cells. However, markers like LDH release, TBARS, BODIPY and ROS were significantly higher due to cisplatin in comparison to Pt coated Au NP.

Conclusions: Pt coated Au NP caused NO-dependent mitochondrial dysfunction and autophagy. Mode of cell death due to NP was much different from ROS-inducing cisplatin.

General significance: Pt coated Au NP offer promising opportunity in cancer therapeutic and warrants advanced study in vivo models of cancer.

Keywords: Anticancer; Autophagy; Necrosis; Nitric oxide; ROS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Autophagy / drug effects
Carcinoma / drug therapy*
Carcinoma / genetics
Carcinoma / pathology
Cell Death / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Cisplatin / pharmacology
Gold / chemistry
Gold / pharmacology
Humans
Hydrogen Peroxide / metabolism
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Metal Nanoparticles / administration & dosage*
Metal Nanoparticles / adverse effects
Metal Nanoparticles / chemistry
Mitochondria / drug effects*
Mitochondria / pathology
Nitric Oxide / pharmacology
Reactive Nitrogen Species / metabolism
Reactive Oxygen Species / metabolism

Substances

Reactive Nitrogen Species
Reactive Oxygen Species
Nitric Oxide
Gold
Hydrogen Peroxide
Cisplatin