2. Academic Validation
  3. The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism

  • Redox Biol. 2024 Jun 18:75:103245. doi: 10.1016/j.redox.2024.103245.
Mengqi Yang 1,  Jiaxin Liu 2,  Jianan Li 2,  Shijun Wen 3,  Yumin Hu 3,  Wenhua Lu 3,  Jinyun Liu 4,  Peng Huang 5,  Panpan Liu 6
Affiliations

Affiliations

  • 1 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Radiation Oncology, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
  • 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
  • 3 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
  • 4 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Metabolic Innovation Center, Zhongshan School of Medicine, Platform of Metabolomics Center for Precision Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: liujinyun86@outlook.com.
  • 5 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Metabolic Innovation Center, Zhongshan School of Medicine, Platform of Metabolomics Center for Precision Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: huangpeng@sysucc.org.cn.
  • 6 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China. Electronic address: liupp@sysucc.org.cn.
PMID: 38909408 DOI: 10.1016/j.redox.2024.103245
Abstract

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple Cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD Enzyme per se was insufficient to cause Cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant Enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic Enzyme GAPDH, leading to a significant depletion of ATP and inhibition of Cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the Anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with Immune Checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

Keywords

ATP; Auranofin; Immune checkpoint; Lymphoma; ROS; TXNRD.

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