Synergistic Radiosensitization by Gold Nanoparticles and the Histone Deacetylase Inhibitor SAHA in 2D and 3D Cancer Cell Cultures.

Nóra Igaz,Dávid Kovács,Mónika Kiricsi,Csaba Vizler,Péter Bélteky,Zsolt Rázga,Katalin Hideghéty,Andrea Buhala,Krisztina Szőke,Zoltán Kónya,Zoltán Varga,László Tiszlavicz

doi:10.3390/nano10010158

Abstract

Radiosensitizing agents are capable of augmenting the damage of ionizing radiation preferentially on cancer cells, thereby increasing the potency and the specificity of radiotherapy. Metal-based nanoparticles have recently gathered ground in radio-enhancement applications, owing to their exceptional competence in amplifying the cell-killing effects of irradiation. Our aim was to examine the radiosensitizing performance of gold nanoparticles (AuNPs) and the chromatin-modifying histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) alone and in combination. We observed that the colony-forming capability of cancer cells decreased significantly and the DNA damage, detected by γH2AX immunostaining, was substantially greater after combinational treatments than upon individual drug exposures followed by irradiation. Synergistic radiosensitizing effects of AuNPs and SAHA were proven on various cell lines, including radioresistant A549 and DU-145 cancer cells. 3D cultures often manifest radio- and drug-resistance, nevertheless, AuNPs in combination with SAHA could effectively enhance the potency of irradiation as the number of viable cells decreased significantly when spheroids received AuNP + SAHA prior to radiotherapy. Our results imply that a relaxed chromatin structure induced by SAHA renders the DNA of cancerous cells more susceptible to the damaging effects of irradiation-triggered, AuNP-released reactive electrons. This feature of AuNPs should be exploited in multimodal treatment approaches.

Highlights

In many cases classical chemotherapy leads to only a moderate success rate while provoking a number of unwanted, life-quality-compromising side effects [1]
We showed that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) enhances the DNA targeting activity and apoptosis-inducing efficacy of AgNPs most probably due to their combined effect on chromatin structure, as substantial amounts of reactive oxygen species generated rapidly by reactive silver ions and released from the AgNP surface caused direct damage on supramolecular structures, including the DNA
We aimed to examine whether HDAC inhibition by suberoylanilide hydroxamic acid (SAHA) and gold nanoparticles are able to potentiate each other’s radiosensitizing features in 2D and 3D cancer cell cultures

Summary

Introduction

In many cases classical chemotherapy leads to only a moderate success rate while provoking a number of unwanted, life-quality-compromising side effects [1]. Administration of radiosensitizing agents—which may or may not have direct anti-cancer effects—augments the efficacy of ionizing radiation on the tumor tissue and at the same time reduces the required dose of the irradiation, the injury of the tumor surrounding normal tissues is significantly attenuated [12]. Such enhancement of irradiation efficiency is commonly achieved by the application of chemical elements with high atomic numbers, typically by high-Z metals.

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