Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1

Journal of Translational Medicine

Research

Yin Liu¹  Tianhe Huang²  Miao Wang²  Tianzi Xu²  Yixin Liu²  Biao Ning²  Yi Li²  Yongchang Wei²  Wenyan She³ 

[1] Department of Hematology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, 430071, Wuhan, Hubei, People’s Republic of China;Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, 430071, Wuhan, Hubei, People’s Republic of China;Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, 430071, Wuhan, Hubei, People’s Republic of China;State Key Laboratory of Virology, College of Chemistry and Molecular Sciences, Wuhan University, No. 299 Bayi Road, Wuchang District, 430072, Wuhan, Hubei, People’s Republic of China;

关键词: Osteosarcoma;    Arsenic;    ROS;    Apoptosis;    PDK-1;   

DOI  :  10.1186/s12967-022-03862-1

 received in 2022-07-16, accepted in 2022-12-29,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundOsteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS.MethodsHere, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo.ResultsAa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model.ConclusionThe study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.

【 授权许可】

CC BY   
© The Author(s) 2023

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