title: Rapid dissolution of ZnO nanocrystals in acidic cancer microenvironment leading to preferential apoptosis.
abstract: The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC(50)∼150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ∼5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival.
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham University, Cochin 682 041, Kerala, India.
authors.forename: Abhilash
authors.initials: A
authors.lastname: Sasidharan
authors.forename: Parwathy
authors.initials: P
authors.lastname: Chandran
authors.forename: Deepthy
authors.initials: D
authors.lastname: Menon
authors.forename: Sreerekha
authors.initials: S
authors.lastname: Raman
authors.forename: Shantikumar
authors.initials: S
authors.lastname: Nair
authors.forename: Manzoor
authors.initials: M
authors.lastname: Koyakutty
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D015034:Zinc Oxide / Q000737:chemistry*
chemical_list: D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D015034:Zinc Oxide