4SC-202 induces apoptosis in myelodysplastic syndromes and the underlying mechanism

  • Am J Transl Res. 2020 Jun 15;12(6):2968-2983.
Weili Wang  1 ,  Zhaoyuan Zhang  2  3  4 ,  Xingyi Kuang  2  3  4 ,  Dan Ma  2  3  4 ,  Jie Xiong  2  3  4 ,  Tingting Lu  2  3  4 ,  Yaming Zhang  2  3  4 ,  Kunling Yu  1  2 ,  Siyu Zhang  1  2 ,  Jishi Wang  2  3  4 ,  Qin Fang  5
Affiliations
  • 1. Department of Pharmacy, Guizhou Medical University Guiyang, P. R. China.
  • 2. Guizhou Province Hematopoietic Stem Cell Transplantation Center, The Affiliated Hospital of Guizhou Medical University Guiyang, P. R. China.
  • 3. Department of Hematology, The Affiliated Hospital of Guizhou Medical University Guiyang, P. R. China.
  • 4. Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province Guiyang, P. R. China.
  • 5. Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University Guiyang, P. R. China.
PMID: 32655823
Abstract

Epigenetic modifications play crucial roles in regulating the self-renewal and differentiation of hematopoiesis. 4SC-202, a novel inhibitor of histone lysine-specific demethylase 1 (LSD1) and class I histone deacetylases (HDACs), is a potential therapeutic agent to treat myelodysplastic syndrome (MDS). However, it remains unclarified of the mechanism of 4SC-202. In the study, we found that 4SC-202 treatment could inhibit cell viability, induce Apoptosis and cause G2/M cell cycle arrest in MDS cell line SKM-1. Heme oxygenase-1 (HO-1) was correlated with disease progression and chemotherapy resistance. Here, we reported that 4SC-202 could down-regulate the expression of HO-1, and up-regulation of HO-1 could significantly attenuate the 4SC-202-induced Apoptosis in SKM-1 cells. In addition, the activation of NF-κB pathway was suppressed by 4SC-202, while up-regulation of HO-1 significantly weakened the 4SC-202-induced suppression of the NF-κB pathway, thereby attenuating the efficacy of 4SC-202. However, down-regulation of HO-1 enhanced the sensitivity of 4SC-202 against SKM-1 cells. Moreover, SKM-1 cells were transfected with HO-1 overexpression lentivirus, subsequently injected into the tail vein of NOD/SCID mice, followed by administration of 4SC-202 in mice. As a result, up-regulation HO-1 could partially attenuate 4SC-202-suppressed MDS cells growth in NOD/SCID mice. In conclusion, 4SC-202 could induce Apoptosis via the NF-κB pathway, and our present finding may provide a novel therapeutic strategy for MDS.

Keywords
4SC-202; NF-κB pathway; apoptosis; class I HDACs; heme oxygenase-1 (HO-1); human histone lysine-specific demethylase 1 (LSD1); myelodysplastic syndrome (MDS).
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