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A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1
Yixin Liu1,2, Wenyan She3, Yi Li1,2
1Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, Hubei, People's Republic of China.
Background:
Osteosarcoma (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.
Methods:
Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo.
Results:
Aa-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.
Conclusion:
The 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.
Insights
A novel organo-arsenic compound, Aa-Z2, effectively inhibits osteosarcoma (OS) by inducing cell death and growth suppression. It targets metabolism and increases reactive oxygen species (ROS), offering a new therapeutic strategy for bone cancer.
Area of Science:
- Oncology
- Metabolic pathways
- Pharmacology
Background:
- Osteosarcoma (OS) is a primary bone cancer with a poor prognosis.
- Metabolic dysregulation is implicated in OS development.
- Arsenic compounds show potential anti-OS activity, but their metabolic targets are underexplored.
Purpose of the Study:
- To investigate the anti-tumour efficacy and mechanism of a novel organo-arsenic compound, Aa-Z2, against osteosarcoma.
- To explore Aa-Z2's effects on cellular metabolism and reactive oxygen species (ROS) generation in OS.
Main Methods:
- In vitro and in vivo studies using osteosarcoma cell lines (143B, HOS) and a xenograft model.
- Analysis of apoptosis, cell cycle arrest, autophagy, ROS levels, mitochondrial membrane potential, and key signaling pathways (PI3K/Akt/mTOR).
- Investigation of the role of pyruvate dehydrogenase kinase 1 (PDK-1) and the effect of ROS scavenger N-acetylcysteine (NAC).
Main Results:
- Aa-Z2 induced osteosarcoma cell apoptosis, G2/M phase arrest, and autophagy via ROS accumulation.
- Elevated ROS promoted caspase cascade and inhibited the PI3K/Akt/mTOR pathway; NAC reversed these effects.
- Aa-Z2 targeted PDK-1, altering mitochondrial function and glucose metabolism to increase ROS; PDK-1 overexpression reduced Aa-Z2 sensitivity.
- Aa-Z2 significantly suppressed tumour growth in vivo.
Conclusions:
- Aa-Z2 demonstrates significant anti-osteosarcoma efficacy through ROS-mediated metabolic reprogramming.
- The findings elucidate Aa-Z2's mechanism, targeting PDK-1 and impacting mitochondrial metabolism.
- This study supports the development of metabolism-targeting drugs for osteosarcoma treatment.
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