title: Phenolcarboxylic acids from medicinal herbs exert anticancer effects through disruption of COX-2 activity.
abstract: Integrated research of herbs and formulas characterized by functions of promoting blood circulation and removing blood stasis is one of the most active fields in traditional Chinese medicine. This paper strives to demonstrate the roles of a homologous series of phenolcarboxylic acids from these medicinal herbs in cancer treatment via targeting cyclooxygenase-2 (COX-2), a well-recognized mediator in tumorigenesis. We selected thirteen typical phenolcarboxylic acids (benzoic acid derivatives, cinnamic acid derivatives and their dehydration-condensation products), and found gallic acid, caffeic acid, danshensu, rosmarinic acid and salvianolic acid B showed 50% inhibitory effects on hCOX-2 activity and A549 cells proliferation. 2D-quantitative method was introduced to describe the potential structural features that contributed to certain bioactivities. We also found these compounds underwent responsible hydrogen bonding to Arg120 and Ser353 in COX-2 active site residues. We further extensively focused on danshensu [d-(+)-β-(3,4-dihydoxy-phenylalanine)] or DSS, which exerted COX-2 dependent anticancer manner. Both genetic and pharmacological inhibition of COX-2 could enhance the ability of DSS inhibiting A549 cells growth. Additionally, COX-2/PGE2/ERK signaling axis was essential for the anticancer effect of DSS. Furthermore, combined treatment with DSS and celecoxib could produce stronger anticancer effects in experimental lung metastasis of A549 cells in vivo. All these findings indicated that phenolcarboxylic acids might possess anticancer effects through jointly targeting COX-2 activity in cancer cells and provided strong evidence in cancer prevention and therapy for the herbs characterized by blood-activating and stasis-resolving functions in clinic.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Aiyun
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: profyinlu@163.com.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010946:Plants, Medicinal / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002264:Carboxylic Acids; D052246:Cyclooxygenase 2 Inhibitors; D004365:Drugs, Chinese Herbal; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Anticancer effects; COX-2; Phenolcarboxylic acids; Traditional Chinese medicine