The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis

Chi Yuan Chen, Shuenn Chen Yang, Kuo Hsiung Lee, Xiaoming Yang, Lin Yi Wei, Lu Ping Chow, Tzu Chien V. Wang, Tse Ming Hong, Jau Chen Lin, Crysline Kuan, Pan Chyr Yang

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19 Citations (Scopus)

Abstract

Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.

Original languageEnglish
Pages (from-to)677-685
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
Publication statusPublished - 2014 Feb 13

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Chen, C. Y., Yang, S. C., Lee, K. H., Yang, X., Wei, L. Y., Chow, L. P., Wang, T. C. V., Hong, T. M., Lin, J. C., Kuan, C., & Yang, P. C. (2014). The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis. Journal of Medicinal Chemistry, 57(3), 677-685. https://doi.org/10.1021/jm401686b