Targeting 3-phosphoinositide-dependent protein kinase 1 associated with drug-resistant renal cell carcinoma using new oridonin analogs

Jiancheng Zhou, Eun Jin Yun, Wei Chen, Ye Ding, Kaijie Wu, Bin Wang, Chunyong Ding, Elizabeth Hernandez, John Santoyo, Rey Chen Pong, Haiying Chen, Dalin He, Jia Zhou, Jer Tsong Hsieh

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The current agents used for renal cell carcinoma (RCC) only exhibit the moderate response rate among patients. Development of drug resistance eventually fuels the need of either more potent drugs or new drugs to target the resistant pathways. Oridonin is a diterpenoid isolated from the Chinese medicinal herb Rabdosia rubescens and has been shown to have antitumor activities in many cancers. We previously developed new synthetic methodologies to modify structurally diversified diterpenoids and designed a series of nitrogen-enriched oridonin analogs. In this study, we screened a variety of oridonin analogs based on their cytotoxicity using MTT assay and identify the most potent candidate, namely, CYD-6-17. CYD-6-17 exhibited a high potency to inhibit the in vitro growth of several drug-resistant RCC cells as well as endothelial cells stimulated by tumor cells at nanomolar range. Delivery of CYD-6-17 significantly inhibited RCC tumor growth using xenograft model. Mechanistically, it targeted the 3-phosphoinositide-dependent protein kinase 1 gene that appeared to be a potent regulator of AKT and was associated with patient survival after targeted therapies. This offers a new rational therapeutic regimen of CYD-6-17 to drug-resistant RCC based on its novel mechanism of action.

Original languageEnglish (US)
Pages (from-to)e2701
JournalCell death & disease
Volume8
Issue number3
DOIs
StatePublished - Mar 23 2017

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Zhou, J., Yun, E. J., Chen, W., Ding, Y., Wu, K., Wang, B., Ding, C., Hernandez, E., Santoyo, J., Pong, R. C., Chen, H., He, D., Zhou, J., & Hsieh, J. T. (2017). Targeting 3-phosphoinositide-dependent protein kinase 1 associated with drug-resistant renal cell carcinoma using new oridonin analogs. Cell death & disease, 8(3), e2701. https://doi.org/10.1038/cddis.2017.121