2. Academic Validation
  3. Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGFβ1 induced lung and tumor fibrosis

Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGFβ1 induced lung and tumor fibrosis

  • Cell Death Dis. 2020 Sep 17;11(9):765. doi: 10.1038/s41419-020-02916-w.
Wentian Zhang  # 1,  Yajie Zhang  # 1,  Tian Tu 2,  Sabastian Schmull 3,  Yu Han 1,  Wenbo Wang 4,  Hecheng Li 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Rd, Shanghai, 200025, China.
  • 2 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 ZhiZaoJu Road, Shanghai, 200011, China.
  • 3 Renji-Med X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu-Jian Road, Shanghai, 200127, China.
  • 4 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 ZhiZaoJu Road, Shanghai, 200011, China. wangwenbo0903@126.com.
  • 5 Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Rd, Shanghai, 200025, China. lihecheng2000@hotmail.com.
  • # Contributed equally.
PMID: 32943605 DOI: 10.1038/s41419-020-02916-w
Abstract

TGFβ1 signaling is a critical driver of collagen accumulation in pulmonary fibrotic diseases and a well-characterized regulator of Cancer associated fibroblasts (CAF) activation in lung Cancer. Myofibroblasts induced by TGFβ1 and other factors are key players in the pathogenesis of lung fibrosis and tumor. Tremendous attention has been gained to targeting myofibroblasts in order to inhibit the progression of fibrosis and myofibroblast-induced tumor progression and metastasis. Here we determined the therapeutic efficacy of simultaneously targeting PI3K and HDAC pathways in lung myofibroblasts and CAF with a single agent and to evaluate biomarkers of treatment response. CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and PI3K/Akt pathway. We investigated its effects in counteracting the activity of TGFβ1-induced myofibroblasts/CAF in regard to cell proliferation, migration, invasion, Apoptosis in vitro antifibrosis efficiency in vivo. We found that CUDC-907 inhibited myofibroblasts/CAF cell proliferation, migration and Apoptosis in a dose-dependent manner and caused cell cycle arrest at G1-S phase. CUDC-907 not only inhibited myofibroblasts markers expression, but also significantly inhibited the phosphorylation level of Akt, mTOR, SMAD2/3, and promoted acetylation of histones. Furthermore, the observed inhibitory effect was also confirmed in bleomycin-induced mice lung fibrosis and nude mouse transplanted tumor model. Overall, these data suggest that dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for TGFβ1-induced lung and tumor fibrosis.

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