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

• Published in: Nature communications Vol. 9; no. 1; pp. 4347 - 11
• Main Authors: Cui, Zhifen, Zhang, Yu, Xia, Kai, Yan, Qinglong, Kong, Huating, Zhang, Jichao, Zuo, Xiaolei, Shi, Jiye, Wang, Lihua, Zhu, Ying, Fan, Chunhai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/2; 147/143; 631/67; 631/80; 639/925; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Apoptosis; Arsenic; Arsenic trioxide; Arsenic Trioxide - administration & dosage; Arsenic Trioxide - adverse effects; Arsenic Trioxide - therapeutic use; Autophagy; Autophagy - drug effects; Carcinoma - drug therapy; Carcinoma - pathology; Cell death; Diamonds; Drug Therapy, Combination; Hematological diseases; Hep G2 Cells; Hepatocytes; Humanities and Social Sciences; Humans; Inhibitors; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Mice; Mice, Nude; multidisciplinary; Nanodiamonds - administration & dosage; Nanodiamonds - adverse effects; Nanodiamonds - therapeutic use; Nanoparticles; Nanostructure; Phagocytosis; Science; Science (multidisciplinary); Solid tumors; Survival; Therapy; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06749-2

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. Arsenic trioxide (ATO) based therapy in solid cancers is limited. Here they repurpose nanodiamonds (NDs) as a safe and potent autophagic inhibitor to improve the efficacy of ATO-based treatment in solid tumors and show the combination therapy to work better in orthotopic liver cancer model.