1. Academic Validation
  2. Gambogenic acid induces cell death in human osteosarcoma through altering iron metabolism, disturbing the redox balance, and activating the P53 signaling pathway

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. 2023 Jun 9;110602. doi: 10.1016/j.cbi.2023.110602.
Zilin Liu 1 Xuezhong Wang 1 Jianping Li 1 Xiaoming Yang 1 Jun Huang 1 Chuang Ji 1 Xuyang Li 1 Lan Li 1 Jianlin Zhou 2 Yong Hu 3
Affiliations

Affiliations

  • 1 Department of Orthopedics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China.
  • 2 Department of Orthopedics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China. Electronic address: zjl13659880625@163.com.
  • 3 Department of Orthopedics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China. Electronic address: hyrm2017@126.com.
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.

Keywords

Apoptosis; Ferroptosis; GPX4; Gambogenic acid; Osteosarcoma; P53.

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