Nanodiamond autophagy inhibitor allosterically improves the arsenical-based therapy of solid tumors

Zhifen Cui,Xiaolei Zuo,Yu Zhang,Chunhai Fan,Ying Zhu,Qinglong Yan,Jichao Zhang,Huating Kong,Kai Xia,Jiye Shi,Lihua Wang

doi:10.1038/s41467-018-06749-2

Abstract

Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; however its efficacy in solid tumors is limited. Here we repurpose nanodiamonds (NDs) as a safe and potent autophagic inhibitor to allosterically improve the therapeutic efficacy of ATO-based treatment in solid tumors. We find that NDs and ATO are physically separate and functionally target different cellular pathways (autophagy vs. apoptosis); whereas their metabolic coupling in human liver carcinoma cells remarkably enhances programmed cell death. Combination therapy in liver tumor mice model results in ~91% carcinoma decrease as compared with ~28% without NDs. Treated mice show 100% survival rate in 150 days with greatly reduced advanced liver carcinoma-associated symptoms, and ~80% of post-therapy mice survive for over 20 weeks. Our work presents a novel strategy to harness the power of nanoparticles to broaden the scope of ATO-based therapy and more generally to fight solid tumors.

Highlights

Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; its efficacy in solid tumors is limited
In the copresence of CQ and NDs, we found that LC3-II increased and more p62 accumulated in cells, as compared to cells treated with NDs alone (Fig. 1c), which further confirmed that NDs functioned as autophagy inhibitors to regulate autophagic flux and autolysosomal efflux
We found that the weight ratio of tumor in NDs–ATO cotreatment group dramatically decreased with time, while that in ATO treatment group exhibited no obvious change with time

Summary

Introduction

Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; its efficacy in solid tumors is limited. Normal University, 500 Dongchuan Road, Shanghai 200241, China These authors contributed : Zhifen Cui, Yu Zhang, Kai Xia, Qinglong Yan. Arsenic trioxide (ATO)-based cancer therapy has attracted intense interest since low concentrations of ATO can selectively induce apoptosis of blood cancer cells[1,2,3]. By screening a library of NAPIs in human liver carcinoma (HepG2) cells, we establish that nanodiamonds (NDs) are a type of safe and potent NAPI, which can allosterically enhance the ATObased therapy in HepG2. Based on this finding, we develop a combination therapy for ATO-based treatment of an orthotopic liver tumor transplantation mice model

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