Induction of mitochondria mediated apoptosis in human ovarian cancer cells by folic acid coated tin oxide nanoparticles.

Demiana H Hanna,Gamal R Saad

doi:10.1371/journal.pone.0258115

Abstract

PurposeThis study aims to prepare folic acid coated tin oxide nanoparticles (FA-SnO2 NPs) for specifically targeting human ovarian cancer cells with minimum side effects against normal cells.MethodsThe prepared FA-SnO2 NPs were characterized by FT-IR, UV-vis spectroscopy, XRD, SEM and TEM. The inhibition effects of FA-SnO2 NPs against SKOV3 cancer cell were tested by MTT and LDH assay. Apoptosis induction in FA-SnO2 NPs treated SKOV3 cells were investigated using Annexin V/PI, AO/EB and Comet assays and the possible mechanisms of the cytotoxic action were studied by Flow cytometry, qRT-PCR, Immunohistochemistry, and Western blotting analyses. The effects of FA-SnO2 NPs on reactive oxygen species generation in SKOV3 cells were also examined. Additionally, the safety of utilization FA-SnO2 NPs were studied in vivo using Wister rats.ResultsThe obtained FA-SnO2 NPs displayed amorphous spherical morphology with an average diameter of 157 nm and a zeta potential value of -24 mV. Comparing to uncoated SnO2 NPs, FA-SnO2 NPs had a superior inhibition effect towards SKOV3 cell growth that was suggested to be mediated through higher reactive oxygen species generation. It was showed that FA-SnO2 NPs increased significantly the % of apoptotic cells in the sub- G1 and G2/M phases with a higher intensity comet nucleus in SKOV3 treated cells. Furthermore, FA-SnO2 NPs was significantly increased the expression levels of P53, Bax, and cleaved Caspase-3 and accompanied with a significant decrease of Bcl-2 in the treated SKOV3 cells.ConclusionOverall, the results suggested that an increase in cellular FA-SnO2 NPs internalization resulted in a significant induced cytotoxicity in SKOV3 cancer cells in dose-dependent mode through ROS-mediated cell apoptosis that may have occurred through mitochondrial pathway. Additionally, the results confirmed the safety of utilization FA-SnO2 NPs against living systems. So, FA-SnO2 NPs with a specific targeting moiety may be a promising therapeutic candidate for human ovarian cancer.

Highlights

Ovarian carcinoma is classified as the seventh most common cause of cancer mortality in women worldwide and the principal cause of death from gynecologic malignancies [1]
We compared between the effects of SnO2 NPs and folic acid (FA)-SnO2 NPs on the cytotoxicity, oxidative stress and apoptosis induction of a human ovarian cancer cell line (SKOV3). we explored that the mechanisms of SKOV3 cell death after exposure to SnO2 NPs and FA-SnO2 NPs were likely to be mediated through reactive oxygen species (ROS) overproduction on time dependent manner
Our current study suggested a beneficial insight into the cellular and molecular events involved in the ovarian cancer cell apoptosis caused by FA-SnO2 NPs at in vitro level

Summary

Introduction

Ovarian carcinoma is classified as the seventh most common cause of cancer mortality in women worldwide and the principal cause of death from gynecologic malignancies [1]. The primary therapy of ovarian cancer is based on a combination of optimum surgical therapy with platinum-based chemotherapy [2]. Some previous studies demonstrated that, nanoparticles (NPs) have different physical and chemical properties, availability, and biocompatibility, resulting in enhanced selectivity against different cancer cells with a fewer side effects against healthy tissues [5,6,7,8,9,10,11]. The potential applications of these NPs for therapeutic purposes in different cancer types can be highly effective through targeting different receptors of cancer surfaces

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