2. Academic Validation
  3. Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor

Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor

  • Biochem Pharmacol. 2024 Mar 21:223:116155. doi: 10.1016/j.bcp.2024.116155.
Xiang Zhang 1,  Ying Lei 2,  Xiang Chen 3,  Jiahuang He 2,  Zitian Liu 4,  Wentao Zhu 4,  Yi Xu 5,  Xuru Jin 6
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Department of Thoracic Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang Province 324000, China.
  • 2 Department of Respiratory and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Ouzhou, Zhejiang Province 324000, China.
  • 3 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China.
  • 5 Department of Science & Technology, Department of Urology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Ouzhou, Zhejiang Province 324000, China. Electronic address: yixu.md@gmail.com.
  • 6 Department of Respiratory and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Ouzhou, Zhejiang Province 324000, China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China. Electronic address: xuru.jin@wmu.edu.cn.
PMID: 38521474 DOI: 10.1016/j.bcp.2024.116155
Abstract

Aurora Kinase (AURK) and heat shock factor 1 (HSF1) are commonly overexpressed in non-small cell lung Cancer (NSCLC), correlating with poor prognosis. This study aims to assess the therapeutic potential of combining the Danusertib (Danu, AURK inhibitor) and KRIBB11 (HSF1 Inhibitor) for NSCLC treatment. The effects of this combination were investigated in A549 cells and a tumor xenograft mouse model. The findings demonstrate that concurrent administration of Danu and KRIBB11 effectively impedes cell proliferation, induces Apoptosis, and triggers G2/M cell cycle arrest. Moreover, the combination treatment upregulates pro-apoptotic proteins (Cleaved-caspase3, Cleaved-PARP, and Bax) while downregulating anti-apoptotic proteins (Bcl-2), as well as G2/M-related proteins (CDC2 and cyclin B1). Additionally, the combination treatment elevates Reactive Oxygen Species (ROS) levels, decreases mitochondrial membrane potential, and activates the DNA damage pathway. Interestingly, we discovered that the PI3K/Akt pathway is involved in mediating the effects of both Danu and KRIBB11. Furthermore, the combination treatment inhibits tumor growth and Akt signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/Akt signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.

Keywords

Aurora kinase; Danusertib; Heat shock factor 1; KRIBB11; Non-small lung cell cancer; PI3K/AKT.

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