The anti-MDR efficacy of YAN against A549/Taxol cells is associated with its inhibition on glycolysis and is further enhanced by 2-deoxy-d-glucose

  • Chem Biol Interact. 2022 Feb 25;354:109843. doi: 10.1016/j.cbi.2022.109843.
Minghuan Gao  1 ,  Yuying Yang  1 ,  Ying Gao  1 ,  Tong Liu  1 ,  Qi Guan  2 ,  Tianhao Zhou  1 ,  Yani Shi  1 ,  Mingjing Hao  1 ,  Zengqiang Li  1 ,  Daiying Zuo  3 ,  Weige Zhang  4 ,  Yingliang Wu  5
Affiliations
  • 1. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 3. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: [email protected].
  • 4. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: [email protected].
  • 5. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 35122754 DOI: 10.1016/j.cbi.2022.109843
Abstract

Aerobic glycolysis is a hallmark of malignant tumor. Here, the hyperactive glycolysis in multidrug-resistant A549/Taxol cells was demonstrated to be essential for maintaining the vigorous cell viability and drug resistance. 5-(4-ethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-amine (YAN), a newly synthesized tubulin inhibitor, could not only inhibit the glycolysis in A549 and A549/Taxol cells through down-regulating the glycolysis-related proteins, but also disrupt the mitochondrial localization of hexokinase-2 (HK-2) which is related with the Apoptosis resistance. The effects of YAN above were relevant to the down-regulation of PI3K-Akt-c-Myc/HIF-1α pathway. Moreover, YAN induced the Reactive Oxygen Species generation in A549 and A549/Taxol cells, which only mediated the Apoptosis in A549 cells. We also showed that 2-DG, the glycolysis inhibitor, synergistically enhanced YAN-triggered Apoptosis in A549/Taxol cells via further suppressing glycolysis and reducing mitotic slippage. Collectively, we illustrate the inhibition effect of YAN on the glycolysis in A549 and A549/Taxol cells, and provide a fresh insight into the mechanism for the development of YAN as a candidate for multidrug resistant Cancer treatment. The finding that 2-DG improved the anti-tumor efficacy of YAN against A549/Taxol cells, offers a reference for solving mitotic slippage-mediated drug resistance.

Keywords
Aerobic glycolysis; Apoptosis; Mitotic slippage; Multidrug resistance; Reactive oxygen species.
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