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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Abietanes / chemistry
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Abietanes / pharmacology*
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Animals
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / pharmacology*
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Antineoplastic Agents, Phytogenic / therapeutic use
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Apoptosis / drug effects
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Autophagy / drug effects
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Benzoquinones / pharmacology*
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Biological Products / chemistry
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Biological Products / pharmacology*
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Biological Products / therapeutic use
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Cell Cycle Checkpoints / drug effects
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Cell Proliferation / drug effects
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Drug Synergism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Lactams, Macrocyclic / pharmacology*
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MAP Kinase Signaling System / drug effects
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MCF-7 Cells
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Mice, Nude
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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TOR Serine-Threonine Kinases / metabolism
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Triazoles / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Abietanes
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Antineoplastic Agents, Phytogenic
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Benzoquinones
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Biological Products
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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STA 9090
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Triazoles
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tanshinone
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tanespimycin
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Protein Kinase C