陆军军医大学学报 (Aug 2023)

Vemurafenib combined with chidamide promotes senescence of secondary acute myeloid leukemia cells

  • ZHOU Qiao,
  • ZHOU Qiao,
  • LIANG Simin,
  • CAI Duo,
  • XIANG Wenqiong,
  • WANG Li

DOI
https://doi.org/10.16016/j.2097-0927.202305030
Journal volume & issue
Vol. 45, no. 16
pp. 1671 – 1681

Abstract

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Objective To explore the effect of vemurafenib (VEM) combined with chidamide (CDM) on cellular senescence in secondary acute myeloid leukemia (sAML). Methods sAML cell lines SKM-1 and MOLM-13 were divided into control group (sAML cells), VEM group (sAML cells treated with VEM), CDM group (sAML cells treated with CDM), and COM group (sAML cells treated with VEM combined with CDM)(n=3). CCK-8 assay was used to measure the viability of sAML cells. Immunofluorescence assay was used to verified the cellular senescence of sAML cells. Flow cytometry was used to detect cell cycle and apoptosis of sAML cells. Network pharmacology and RT-qPCR were used to analyze and verify the mechanism of VEM combined with CDM. Results VEM inhibited the proliferation of sAML cells lines in a time- and dose-dependent manner(P < 0.05), the half-maximal inhibitory concentration (IC50) of VEM on SKM-1 and MOLM-13 cells was 24.15±1.18 and 11.30±0.38 μmol/L(P < 0.0001), respectively. VEM (SKM-1: 1/3 IC50-VEM, MOLM-13: 1/2 IC50-VEM) combined with CDM synergistically promoted sAML cellular senescence by upregulating TRF2 and Lamin B1, characterized cycle stagnation in G0/G1 phase(P < 0.05), inhibiting cell proliferation(P < 0.01) and promoting cell apoptosis (P < 0.05). Swiss Target Predict, TargetNe, SEA and PharmMapper discovered the core targets and signaling pathways of VEM collaborating with CDM. RT-qPCR verified that VEM collaborated with CDM to promote senescence of sAML cells through inhibiting PI3K-AKT and MAPK signaling pathways(P < 0.05). Conclusion VEM combined with CDM can induce cellular senescence of sAML cells by downregulating PI3K-AKT and MAPK signaling pathways, inhibiting proliferation and promoting apoptosis of sAML cells. VEM combined with CDM might be a new regime for patients with sAML.

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