The Effects of TiO2 Nanoparticles on Cisplatin Cytotoxicity in Cancer Cell Lines.

Basma Salama,El-Said El-Sherbini,Koki Kanehira,Akiyoshi Taniguchi,Mohamed El-Adl,Gehad El-Sayed

doi:10.3390/ijms21020605

Abstract

There have been many studies on improving the efficacy of cisplatin and on identifying safe compounds that can overcome multi-drug resistance (MDR) acquired by cancer cells. Our previous research showed that polyethylene glycol-modified titanium dioxide nanoparticles (TiO2 PEG NPs) affect cell membrane receptors, resulting in their aggregation, altered localization and downregulation. TiO2 PEG NPs may affect P-glycoprotein (P-gp), a membrane efflux channel involved in MDR. In this study, we investigated the effect of TiO2 PEG NPs on cisplatin cytotoxicity. We used HepG2 cells, which highly express P-gp and A431 cells, which show low expression of P-gp. The results showed that 10 µg/mL 100 nm TiO2 PEG NPs increased intracellular cisplatin levels and cytotoxicity in HepG2 cells but not in A431 cells. TiO2 PEG NPs treatment decreased the expression level of P-gp in HepG2 cells. Our findings indicate that TiO2 PEG NPs enhance cisplatin cytotoxicity by down regulating P-gp and that TiO2 PEG NPs are promising candidates for inhibiting P-gp and reversing drug resistance acquired by cancer cells.

Highlights

Cisplatin is one of the most effective and widely used chemotherapeutic agents in the treatment of solid tumors, including bladder, lung, head and neck, ovarian and testicular cancers [1]
The results suggested that TiO2 PEG NPs may affect the function of P-gp and here, we investigated the effect of TiO2 PEG NPs on cisplatin cytotoxicity
We evaluated the effect of TiO2 PEG NPs on cisplatin cytotoxicity by treating HepG2 and A431 cells with the IC50 of cisplatin mixed with different concentrations of 100 nm, 200 nm and 300 nm TiO2 PEG NPs

Summary

Introduction

Cisplatin is one of the most effective and widely used chemotherapeutic agents in the treatment of solid tumors, including bladder, lung, head and neck, ovarian and testicular cancers [1]. Multi-drug resistance (MDR) is an important phenomenon in which many types of cancer cells acquire resistance against a broad range of structurally distinct anticancer drugs [3]. P-glycoprotein (P-gp), called multi-drug resistance protein 1 (MDR1), is considered the most important membrane efflux pump involved in MDR [4]. The TMDs form channels for the efflux of substrate drugs, whereas the NBDs are exposed to the cytoplasm and participate in ATP binding and hydrolysis [6]. In cell lines that express P-gp, trafficking from the endoplasmic reticulum and the Golgi apparatus is transient and P-gp is rapidly transported to the cell membrane by endosomes, explaining why P-gp is primarily localized on cell surfaces rather than in the cytoplasm [10]. It was previously reported that P-gp has a relatively long half-life on the cell membrane (14–17 h), followed by lysosomal degradation, and several compounds could affect the half-life of P-gp and increase its internalization by lysosomes [11]

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