Cryptotanshinone Reverses Corticosteroid Insensitivity by Inhibition of Phosphoinositide-3-Kinase-δ in Chronic Obstructive Pulmonary Disease

Int J Chron Obstruct Pulmon Dis. 2023 May 6:18:797-809. doi: 10.2147/COPD.S405757. eCollection 2023.

Abstract

Purpose: Corticosteroid insensitivity has become a major barrier in the treatment of chronic obstructive pulmonary disease (COPD). It is known that oxidative stress reduces the expression and activity of histone deacetylase (HDAC)-2 by activating phosphoinositide-3-kinase-δ(PI3Kδ)/Akt pathway, which is a common mechanism. The aim of this study was to investigate whether cryptotanshinone (CPT) can improve corticosteroid sensitivity and to investigate the molecular mechanisms by which this occurs.

Patients and methods: Corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) collected from COPD patients, or in human monocytic U937 monocytic cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-α (TNFα)-induced interleukin 8 (IL-8) production in the presence or absence of cryptotanshinone. PI3K/Akt activity (measured as the relative ratio of phosphorylated Akt at Ser-473 to total Akt) and HDAC2 expression levels were determined by western blotting. HDAC activity was evaluated by a Fluo-Lys HDAC activity assay kit in U937 monocytic cells.

Results: Both PBMCs in patients with COPD and U937 cells exposed to CSE were found to be insensitive to dexamethasone, accompanied by increased phosphorylated Akt (pAkt) and decreased HDAC2 protein expression. The pretreatment of cryptotanshinone restored their sensitivity to dexamethasone, and simultaneously downregulated the level of phosphorylated Akt and upregulated the level of HDAC2 protein. Pretreatment with cryptotanshinone or IC87114 reversed the decrease in HDAC activity in CSE-stimulated U937 cells.

Conclusion: Cryptotanshinone restores corticosteroid sensitivity induced by oxidative stress via inhibition of PI3Kδ and is a potential treatment for corticosteroid-insensitive diseases such as COPD.

Keywords: chronic obstructive pulmonary disease; corticosteroid insensitivity; cryptotanshinone; histone deacetylase 2; phosphoinositide-3-kinase-δ.

MeSH terms

  • Adrenal Cortex Hormones / pharmacology
  • Dexamethasone / pharmacology
  • Histone Deacetylase 2 / metabolism
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositols / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Disease, Chronic Obstructive* / metabolism

Substances

  • cryptotanshinone
  • Phosphatidylinositol 3-Kinase
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Adrenal Cortex Hormones
  • Dexamethasone
  • Phosphatidylinositols
  • Histone Deacetylase 2

Grants and funding

This work was supported by grants from the Natural Science Foundation of Huaian, Jiangsu, China (No. HAB202115 and No. HAB202073) and Natural Science Research Projects in Jiangsu Universities, Jiangsu, China (21KJD310002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.