title: Proapoptotic and TRAIL-sensitizing constituents isolated from Salvia militiorrhiza (Danshen).
abstract: Natural compounds isolated from medicinal plants are invaluable resources for drug discovery. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent unique by its cancer cell-specific proapoptotic action, but its potential is heavily curbed by acquired resistance. We herein reported for the first time the identification of cytotoxic and TRAIL-sensitizing components of Salvia miltiorrhiza (Danshen), a traditional medicinal plant effective for treating cardiovascular disorders. Specifically, we found that the ethanol extract and its group 5 fraction of S. miltiorrhiza showed evident cytotoxicity against the human lung adenocarcinoma cell line A549 and ovarian adenocarcinoma cell line TOV-21G in a concentration-dependent manner. Likewise, a dose-dependent cytotoxicity was exerted by the standard solutions of cryptotanshinone, tanshinone I and tanshinone IIA, the major components of the group 5 fraction, where tanshinone IIA were most potent and displayed an IC₅₀ of 2.00 ± 0.36 μM and 2.75 ± 0.23 μM for A549 and TOV-21G, respectively. Induction of apoptosis represents an essential mechanism underlying tanshinone IIA-mediated cytotoxic action, as evidenced by the proteolytic processing of PARP upon tanshinone IIA stimulation and, importantly, a marked rescue of the viability of tanshinone IIA-treated cells when co-treatment with the pan-caspase inhibitor z-VAD-fmk. Noteworthy, stimulation with cryptotanshinone, tanshinone I or tanshinone IIA all effectively potentiated TRAIL to reduce viability and inhibit the colony formation capacity of TRAIL-resistant TOV-21G and SKOV3. Collectively, we revealed the proapoptotic and TRAIL-sensitizing components of S. miltiorrhiza and further implicated the potential of developing these active compounds as monotherapeutic agent or TRAIL-based therapy for cancer chemoprevention or chemotherapy.
authors: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, 666 Buzih Road, Taichung 40601, Taiwan.
authors: Chia-Che
authors: CC
authors: Chang
authors: Jui-Sheng
authors: JS
authors: Lai
authors: Chi-Shiuan
authors: CS
authors: Tsai
authors: Song-Wei
authors: SW
authors: Ma
authors: Jyun-Yi
authors: JY
authors: Lin
authors: Lan-Ru
authors: LR
authors: Huang
authors: Chien-Hsing
authors: CH
authors: Lu
authors: En-Chih
authors: EC
authors: Liao
authors: Tsing-Fen
authors: TF
authors: Ho
mesh_terms: D045784:Abietanes / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010616:Phenanthrenes / Q000494:pharmacology; D010618:Phenanthrolines / Q000737:chemistry* / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000378:metabolism*
chemical_list: D045784:Abietanes; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D010618:Phenanthrolines; D010936:Plant Extracts; D053221:TNF-Related Apoptosis-Inducing Ligand; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C021751:tanshinone; C028972:dan-shen root extract; C037886:cryptotanshinone; D011065:Poly(ADP-ribose) Polymerases
keywords: Cryptotanshinone; Danshen; Ovarian cancer; PARP; TRAIL; Tanshinone I; Tanshinone IIA; Tumor necrosis factor-related apoptosis-inducing ligand; poly(ADP-ribose) polymerase; tumor necrosis factor-related apoptosis-inducing ligand