Hinokitiol-Loaded Mesoporous Calcium Silicate Nanoparticles Induce Apoptotic Cell Death through Regulation of the Function of MDR1 in Lung Adenocarcinoma Cells.

Yu-Fang Shen,Chia-Che Ho,Kan Wang,Ming-You Shie,Hsin-Yuan Fang

doi:10.3390/ma9050306

Abstract

Hinokitiol is a tropolone-related compound found in heartwood cupressaceous plants. Hinokitiol slows the growth of a variety of cancers through inhibition of cell proliferation. The low water solubility of hinokitiol leads to less bioavailability. This has been highlighted as a major limiting factor. In this study, mesoporous calcium silicate (MCS) nanoparticles, both pure and hinokitiol-loaded, were synthesized and their effects on A549 cells were analyzed. The results indicate that Hino-MCS nanoparticles induce apoptosis in higher concentration loads (>12.5 μg/mL) for A549 cells. Hino-MCS nanoparticles suppress gene and protein expression levels of multiple drug resistance protein 1 (MDR1). In addition, both the activity and the expression levels of caspase-3/-9 were measured in Hino-MCS nanoparticle-treated A549 cells. The Hino-MCS nanoparticles-triggered apoptosis was blocked by inhibitors of pan-caspase, caspase-3/-9, and antioxidant agents (N-acetylcysteine; NAC). The Hino-MCS nanoparticles enhance reactive oxygen species production and the protein expression levels of caspase-3/-9. Our data suggest that Hino-MCS nanoparticles trigger an intrinsic apoptotic pathway through regulating the function of MDR1 and the production of reactive oxygen species in A549 cells. Therefore, we believe that Hino-MCS nanoparticles may be efficacious in the treatment of drug-resistant human lung cancer in the future.

Highlights

Drug delivery is an important method for targeted tumor therapy, and the bioactivity of materials has great importance for promoting tissue regeneration [1,2,3,4]
This study examined the molecular mechanisms triggered by Hino-mesoporous calcium silicate (MCS) in the lung cancer cell line that was established in our laboratory and investigated the relationship between Hino-MCS concentration and the expression level of multiple drug resistance protein 1 (MDR1), which is correlated with chemo-resistance in lung cancer [27] and is an important protein of the cell membrane that pumps many foreign substances out of cells
Our average particle sizes of mesoporous calcium silicate nanoparticles and hinokitiol-loaded mesoporous calcium mesoporous calcium silicate nanoparticles are lower than 440 nm

Summary

Introduction

Drug delivery is an important method for targeted tumor therapy, and the bioactivity of materials has great importance for promoting tissue regeneration [1,2,3,4]. In most studies in this field, enzymes are entrapped in sol-gel silica matrices or mesoporous silica structures [5]. Several studies have proven that mesoporous silica (SiO2 ). Nanoparticles may be used as drug delivery carriers with release kinetics that can be controlled by adjusting the internal and mesopores’ hollow microstructures [6,7,8]. Because of their enriched surface hydroxyl groups, the mesoporous SiO2 nanoparticle can be modified for further application, and have low toxicity for use in biomedical work [9].

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