論文

国際誌
2022年7月24日

Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast.

Cancer science
  • Kosuke Ochi
  • Ken Suzawa
  • Yin Min Thu
  • Fumiaki Takatsu
  • Shimpei Tsudaka
  • Yidan Zhu
  • Kentaro Nakata
  • Tatsuaki Takeda
  • Kazuhiko Shien
  • Hiromasa Yamamoto
  • Mikio Okazaki
  • Seiichiro Sugimoto
  • Tadahiko Shien
  • Yoshiharu Okamoto
  • Shuta Tomida
  • Shinichi Toyooka
  • 全て表示

113
10
開始ページ
3428
終了ページ
3436
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1111/cas.15502

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were co-cultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including of EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer- CAF interaction.

リンク情報
DOI
https://doi.org/10.1111/cas.15502
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/35871750
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9530873
ID情報
  • DOI : 10.1111/cas.15502
  • PubMed ID : 35871750
  • PubMed Central 記事ID : PMC9530873

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