1. Academic Validation
  2. Novel vandetanib derivative inhibited proliferation and promoted apoptosis of cancer cells under normoxia and hypoxia

Novel vandetanib derivative inhibited proliferation and promoted apoptosis of cancer cells under normoxia and hypoxia

  • Eur J Pharmacol. 2022 May 5;922:174907. doi: 10.1016/j.ejphar.2022.174907.
Lijuan Yin 1 Jing Zhan 2 Hai Liao 2 Wentao Qiu 1 Wenbin Hou 3 Su Li 4 Jianping Zhang 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 2 State Key Laboratory Of Oncology In South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 3 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300000, China. Electronic address: hou-zhang@126.com.
  • 4 State Key Laboratory Of Oncology In South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. Electronic address: lisu@sysucc.org.cn.
  • 5 College of Pharmacy, Jinan University, Guangzhou, 510632, China. Electronic address: zhangjessica88@qq.com.
Abstract

Over-expressions of epidermal growth factor receptor and vascular endothelial growth factor receptor were frequently associated with the metastasis of solid tumors. Vandetanib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor and vascular endothelial growth factor receptor, was broadly effective in treating a variety of human solid tumors. The compelling evidence that hypoxia is involved in tumor resistance to Cancer therapy. Hypoxia-inducible factor (HIF-1α), a major transcription factor in response to hypoxia, has been considered as a promising specific target for Cancer therapy. We reported a stronger vandetanib derivative, compound 39, which was more potently decreased viability of A549, HT-29, MCF-7, HepG2, and HeLa cells than its parent compound vandetanib. Remarkable hypoxia-selectivity was observed in A549 cells (IC50 = 1.55 ± 0.23 μM under normoxia and 0.31 ± 0.06 μM under hypoxia, respectively) and HT-29 cells (IC50 = 12.89 ± 2.15 μM under normoxia and 3.47 ± 0.79 μM under hypoxia, respectively). The Apoptosis of A549 and HT-29 cells induced by compound 39 were detected by flow cytometry. Western blot analysis demonstrated that compound 39 significantly down-regulated the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein and up-regulated the expression of pro-apoptotic BCL2-Associated X (Bax) protein as well as promoted the cleavage of poly (ADP-ribose) polymerase PARP. HIF-1α was down-regulated by compound 39 in A549 and HT-29 cells under hypoxia. We also found that the depletion of intracellular Reduced Glutathione (GSH) as well as production of Reactive Oxygen Species (ROS) were critical for compound 39-mediated cell death.

Keywords

Compound 39; Cytotoxicity; Hypoxia; Reactive oxygen species; Reduced glutathione.

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