Abstract
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 subED50 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.
Highlights
Chinese materia medica (CMM) holds great potential to improve people’s health and wellness and needs rigorous scientific data and deeper knowledge to demonstrate its pharmacological significance at a molecular level [1]
Neutrophil extracellular traps (NETs) formation that can be suicidal to neutrophils, or termed as “NETosis,” has been previously recognized as innate immunity fighting extracellular pathogens and implicated in hematogenous metastasis mediated by tumor-associated thrombosis [10, 11]
Though the log-rank test of survival analysis was not statistically significant, we observed that all animals died within 3.5 months, among which those animals that received paclitaxel and Danshen injection (DSI) potentially prolonged survival with 90 and 91 days of median survival time compared with 79 days of that from the control group (Figure 1(f))
Summary
Chinese materia medica (CMM) holds great potential to improve people’s health and wellness and needs rigorous scientific data and deeper knowledge to demonstrate its pharmacological significance at a molecular level [1]. Danshen is a highly ranked CMM represented in clinical prescriptions to treat advanced tumor patients with blood stasis syndrome [5]. NET formation that can be suicidal to neutrophils, or termed as “NETosis,” has been previously recognized as innate immunity fighting extracellular pathogens and implicated in hematogenous metastasis mediated by tumor-associated thrombosis [10, 11]. This is of high interest for abrogating metastasis by targeting NETosis [12, 13]
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