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. [email protected].
  • 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. [email protected].
  • 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. [email protected].
  • # 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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