2. Academic Validation
  3. Inhibition of lysine-specific demethylase 1 enhances the sensitivity of the chemotherapeutic drug doxorubicin in gastric cancer cell

Inhibition of lysine-specific demethylase 1 enhances the sensitivity of the chemotherapeutic drug doxorubicin in gastric cancer cell

  • Mol Biol Rep. 2022 Nov 9. doi: 10.1007/s11033-022-07960-7.
Xu-Yang Zhang # 1,  Pan Hao # 1,  Jun-Wei Wang 1,  Wen Zhao 2,  Hong-Min Liu 3,  Peng-Xing He 4
Affiliations

Affiliations

  • 1 Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 450001, Zhengzhou, China.
  • 2 Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 450001, Zhengzhou, China. zhaowen100@139.com.
  • 3 Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 450001, Zhengzhou, China. liuhm@zzu.edu.cn.
  • 4 Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 450001, Zhengzhou, China. hepengxing@zzu.edu.cn.
  • # Contributed equally.
PMID: 36352181 DOI: 10.1007/s11033-022-07960-7
Abstract

Aim: Lysine-Specific Demethylase 1 (LSD1) inhibitors have been developed and reached the clinic, but its effect in combination with cytotoxic chemotherapy is unclear. Here, we investigated the anti-tumor effect of LSD1 inhibitor GSK-LSD1 and its anti-tumor effect with the DNA damage drug doxorubicin (DOX) in gastric Cancer (GC) cells.

Methods: Cells were treated with different concentrations of GSK-LSD1 to examine the anti-tumor effect versus cell viability by MTT and cell cycle arrest by flow cytometry. To explore whether LSD1 inhibitors can increase the anti-tumor effect of DNA damage drugs, cells were treated with DOX for 48 h after pretreatment with GSK-LSD1 for 48 h. Cell viability was detected by MTT and apoptosis-related proteins were examined by Western blot. Furthermore, anti-tumor efficacy of combination GSK-LSD1 with DOX was also measured in MGC-803 xenografts model in nude mice.

Results: The results showed that LSD1 was highly expressed in GC cell lines. Inhibition of LSD1 has a weak effect on cell viability and cell cycle. Moreover, LSD1 inhibitors pretreatment could significantly increase the anti-tumor effect of DOX. Further study found that inhibition of LSD1 can significantly enhance DOX-induced the Apoptosis, accompanied by down-regulation of antiapoptotic Bcl-2 expression and up-regulation of proapoptotic Bax expression. We also confirmed that inhibition of LSD1 can sensitize the anti-tumor effect of DOX in vivo.

Conclusion: Our findings suggest that the LSD1 inhibitor GSK-LSD1 has a weak inhibitory effect on the viability and cell cycle of GC cells, but can enhance the sensitivity of DOX.

Keywords

DOX; GSK-LSD1; Gastric cancer; LSD1; Sensitivity.

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