title: Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways.
abstract: Cancer related inflammation (CRI) is now recognized as the seventh hallmark in the pathogenesis of many types of malignancies. Paeonol, a natural phenolic component isolated from the root bark of Paeonia moutan, has significant anti-inflammatory activity. Recently, accumulating body of research has revealed potent anti-tumor effects mediated by paeonol. However, little is known about its anticancer mechanism on the basis of CRI. In this study, we observed that paeonol exerted direct anticancer activity through inhibition of cell proliferation, induction of apoptosis, and evident anti-inflammatory effects by reducing proinflammatory cytokines secretion (TNF-α, IL-1β, IL-6, and TGF-β) in the conditioned medium of B16F10 mouse melanoma cells. Interestingly, we found that paeonol significantly reversed motility phenotypes in TNF-α- or IL-6-induced B16F10 singe cell and collective migration and invasion in vitro, which were related to affecting epithelial-to-mesenchymal transition (EMT) makers and MMPs expression. In particular, paeonol disrupted both TNF-α-activated NF-κB and IL-6-activated STAT3 signaling pathways in B16F10 cells. EMSA and luciferase assays showed that paeonol abrogated NF-κB binding and NF-κB-driven promoter activity in the presence of TNF-α. Finally, we showed that paeonol attenuated B16F10 spontaneous lung metastases in C57/BL6J mice with down-regulated levels of serum proinflammatory cytokines. Therefore, paeonol possessed antitumor activity in melanoma cells and mice model by interruption of the aggressive feedback through proinflammatory cytokines mediated NF-κB and STAT3 signaling activation. These findings provide a novel treatment strategy that paeonol might be a promising versatile adjuvant therapy for cancer related inflammation.
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.|Department of Pharmacy, Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Pharmacy, Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China.
authors.forename: Tianlu
authors.initials: T
authors.lastname: Shi
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.|Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Aiyun
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Pharmacy, Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.|Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000098:Acetophenones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000098:Acetophenones; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C013638:paeonol
keywords: B16F10 mouse melanoma; NF-κB; STAT3; cell invasion; cell migration; paeonol