Gambogenic acid induces cell death in human osteosarcoma through altering iron metabolism, disturbing the redox balance, and activating the P53 signaling pathway.
Chem Biol Interact
; 382: 110602, 2023 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-37302459
ABSTRACT
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents with extremely poor prognosis. Gambogenic acid (GNA), one of the major bioactive ingredients isolated from Gamboge, has been shown to possess a multipotent antitumor effect, its activity on OS remains unclear yet. In this study, we found that GNA could trigger multiple cell death modalities, including ferroptosis and apoptosis in human OS cells, reduce the cell viability, inhibit the proliferation and invasiveness. Furthermore, GNA provoked oxidative stress leading to GSH depletion-inducing ROS generation and lipid peroxidation, altered iron metabolism represented by the induction of labile iron, mitochondrial membrane potential decreased, mitochondrial morphological changed, decreased the cell viability. In addition, ferroptosis inhibitors (Fer-1) and apoptosis inhibitors (NAC) can partially reversed GNA' s effects on OS cells. Further investigation showed that GNA augmented the expression of P53, bax, caspase 3 and caspase 9 and decreased the expression of Bcl-2, SLC7A11 and glutathione peroxidase-4 (GPX4). In vivo, GNA was showed to delay tumor growth significantly in axenograft osteosarcoma mouse model. In conclusion, this study reveals that GNA simultaneously triggers ferroptosis and apoptosis in human OS cells by inducing oxidative stress via the P53/SLC7A11/GPX4 axis.
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Base de dados:
MEDLINE
Assunto principal:
Osteossarcoma
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Proteína Supressora de Tumor p53
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article