2. Academic Validation
  3. The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG

The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG

  • Cell Death Dis. 2018 Feb 7;9(2):165. doi: 10.1038/s41419-017-0247-5.
Chao Lv 1,  Hua-Wu Zeng 2,  Jin-Xin Wang 2,  Xing Yuan 2,  Chuang Zhang 3,  Ting Fang 4,  Pei-Ming Yang 1,  Tong Wu 1,  Yu-Dong Zhou 5 6,  Dale G Nagle 5 7,  Wei-Dong Zhang 8 9
Affiliations

Affiliations

  • 1 Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P.R. China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China.
  • 3 School of Pharmaceutical Sciences, Zhengzhou University, Henan, 450001, P.R. China.
  • 4 School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, 350108, P.R. China.
  • 5 Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6 Department of Chemistry and Biochemistry, College of Liberal Arts, University of Mississippi, University, Mississippi, MS, 38677-1848, USA.
  • 7 Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, MS, 38677-1848, USA.
  • 8 Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P.R. China. [email protected].
  • 9 School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China. [email protected].
PMID: 29416003 DOI: 10.1038/s41419-017-0247-5
Abstract

Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms ζ and ε. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (HSP90), it synergistically enhanced the antitumor efficacy of the HSP90 inhibitors 17-AAG and ganetespib in human breast Cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and Autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA.

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