PMID- 30210653 OWN - NLM STAT- MEDLINE DCOM- 20181218 LR - 20181218 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2018 DP - 2018 TI - Polypharmacological Profiles Underlying the Antitumor Property of Salvia miltiorrhiza Root (Danshen) Interfering with NOX-Dependent Neutrophil Extracellular Traps. PG - 4908328 LID - 10.1155/2018/4908328 [doi] LID - 4908328 AB - Danshen, the dried root of Salvia miltiorrhiza, one of the most investigated medicinal plants with well-defined phytochemical constituents, has shown prominent clinical outcomes for antioxidant, anti-inflammatory, and anticoagulant activities to attain vascular protection and additional benefits for cancer therapy. More recently, activation of neutrophil and excessive formation of neutrophil extracellular traps (NETs) have been observed in pathological conditions of metastatic cancers; thus, we hypothesized that suppression of NETs could account for an essential cellular event underlying Danshen-mediated reduction of the incidence of metastasis. Using an experimental pulmonary metastases model of red fluorescent protein- (RFP-) labeled gastric cancer cells in combination with macroscopic ex vivo live-imaging system, our data indicated that Danshen impaired the fluorescent intensity and quantity of metastatic nodules. Moreover, Danshen could prevent neutrophil trafficking to the metastatic sites with decreased plasma levels of neutrophil elastase (NE) and procoagulant potential featured by fibrinogen. We further established phorbol 12-myristate 13-acetate- (PMA-) induced NET formation of human neutrophils and screened representative active compounds derived from the hydrophilic and hydrophobic fractions of Danshen using qualitative and quantitative methods. As a result, we found that salvianolic acid B (Sal B) and 15,16-dihydrotanshinone I (DHT I) exhibited superior inhibitory activities on NET formation and significantly attenuated the levels of citrullinated histone H3 (citH3), a biomarker for NET formation. Multitarget biochemical assays demonstrated that Sal B and DHT I distinctly modulated the enzymatic cascade involved in NET formation. Sal B and DHT I could disrupt NET formation at the earlier stage by blocking the activities of myeloperoxidase (MPO) and NADPH oxidase (NOX), respectively. Lastly, combining treatment of Sal B and DHT I under subED(50) doses displayed remarkable synergism effect on NET inhibition. Altogether, these data provide insight into how promiscuous compounds from herbal medicine can be effectively targeted NETs towards hematogenous metastasis of certain tumors. FAU - Tao, Li AU - Tao L AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Xu, Min AU - Xu M AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Dai, Xiaojun AU - Dai X AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. AD - Yangzhou Hospital of Chinese Medicine, Yangzhou, Jiangsu 225009, China. FAU - Ni, Tengyang AU - Ni T AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Li, Dan AU - Li D AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Jin, Feng AU - Jin F AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Wang, Haibo AU - Wang H AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Tao, Lide AU - Tao L AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. AD - Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225001, China. FAU - Pan, Bo AU - Pan B AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Woodgett, James R AU - Woodgett JR AD - Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada M5G 1X5. AD - Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1X5. FAU - Qian, Yayun AU - Qian Y AUID- ORCID: 0000-0002-3458-3377 AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. FAU - Liu, Yanqing AU - Liu Y AUID- ORCID: 0000-0001-6812-2811 AD - College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China. AD - The State Administration of Traditional Chinese Medicine Key Laboratory of Toxic Pathogens-Based Therapeutic Approaches of Gastric Cancer, Yangzhou University, Yangzhou, Jiangsu 225009, China. LA - eng PT - Journal Article DEP - 20180819 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 SB - IM MH - Animals MH - Extracellular Traps/*genetics MH - Female MH - Humans MH - Mice, Inbred BALB C MH - Mice, Nude MH - Neutrophils/*metabolism MH - Salvia miltiorrhiza/*chemistry PMC - PMC6120273 EDAT- 2018/09/14 06:00 MHDA- 2018/12/19 06:00 PMCR- 2018/08/19 CRDT- 2018/09/14 06:00 PHST- 2018/02/01 00:00 [received] PHST- 2018/05/04 00:00 [revised] PHST- 2018/06/06 00:00 [accepted] PHST- 2018/09/14 06:00 [entrez] PHST- 2018/09/14 06:00 [pubmed] PHST- 2018/12/19 06:00 [medline] PHST- 2018/08/19 00:00 [pmc-release] AID - 10.1155/2018/4908328 [doi] PST - epublish SO - Oxid Med Cell Longev. 2018 Aug 19;2018:4908328. doi: 10.1155/2018/4908328. eCollection 2018.