title: The Combination of Three Natural Compounds Effectively Prevented Lung Carcinogenesis by Optimal Wound Healing.
abstract: The tumor stroma has been described as "normal wound healing gone awry". We explored whether the restoration of a wound healing-like microenvironment may facilitate tumor healing. Firstly, we screened three natural compounds (shikonin, notoginsenoside R1 and aconitine) from wound healing agents and evaluated the efficacies of wound healing microenvironment for limiting single agent-elicited carcinogenesis and two-stage carcinogenesis. The results showed that three compounds used alone could promote wound healing but had unfavorable efficacy to exert wound healing, and that the combination of three compounds made up treatment disadvantage of a single compound in wound healing and led to optimal wound healing. Although individual treatment with these agents may prevent cancer, they were not effective for the treatment of established tumors. However, combination treatment with these three compounds almost completely prevented urethane-induced lung carcinogenesis and reduced tumor burden. Different from previous studies, we found that urethane-induced lung carcinogenesis was associated with lung injury independent of pulmonary inflammation. LPS-induced pulmonary inflammation did not increase lung carcinogenesis, whereas decreased pulmonary inflammation by macrophage depletion promoted lung carcinogenesis. In addition, urethane damaged wound healing in skin excision wound model, reversed lung carcinogenic efficacy by the combination of three compounds was consistent with skin wound healing. Further, the combination of these three agents reduced the number of lung cancer stem cells (CSCs) by inducing cell differentiation, restoration of gap junction intercellular communication (GJIC) and blockade of the epithelial-to-mesenchymal transition (EMT). Our results suggest that restoration of a wound healing microenvironment represents an effective strategy for cancer prevention.
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Linxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Ma
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Cao
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Yaqiu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Geng
authors.affiliation: Department of Oncology, The first hospital Affiliated to Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Han
authors.affiliation: Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
authors.forename: Gangjun
authors.initials: G
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D055370:Lung Injury / Q000150:complications / Q000473:pathology; D008175:Lung Neoplasms / Q000150:complications / Q000473:pathology* / Q000517:prevention & control*; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects; D014520:Urethane; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D001688:Biological Products; D014520:Urethane