title: Honokiol, a phytochemical from the Magnolia plant, inhibits photocarcinogenesis by targeting UVB-induced inflammatory mediators and cell cycle regulators: development of topical formulation.
abstract: To develop newer and more effective chemopreventive agents for skin cancer, we assessed the effect of honokiol, a phytochemical from the Magnolia plant, on ultraviolet (UV) radiation-induced skin tumorigenesis using the SKH-1 hairless mouse model. Topical treatment of mice with honokiol in a hydrophilic cream-based topical formulation before or after UVB (180 mJ/cm(2)) irradiation resulted in a significant protection against photocarcinogenesis in terms of tumor multiplicity (28-60%, P < 0.05 to <0.001) and tumor volume per tumor-bearing mouse (33-80%, P < 0.05 to 0.001, n = 20). Honokiol also inhibited and delayed the malignant progression of papillomas to carcinomas. To investigate the in vivo molecular targets of honokiol efficacy, tumors and tumor-uninvolved skin samples from the tumor-bearing mice were analyzed for inflammatory mediators, cell cycle regulators and survival signals using immunostaining, western blotting and enzyme-linked immunosorbent assay. Treatment with honokiol significantly inhibited UVB-induced expression of cyclooxygenase-2, prostaglandin E(2) (P < 0.001), proliferating cell nuclear antigen and proinflammatory cytokines, such as tumor necrosis factor-α (P < 0.001), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.001) in the skin as well as in skin tumors. Western blot analysis revealed that honokiol: (i) inhibited the levels of cyclins D1, D2 and E and associated cyclin-dependent kinases (CDKs)2, CDK4 and CDK6, (ii) upregulated Cip/p21 and Kip/p27 and (iii) inhibited the levels of phosphatidylinositol 3-kinase and the phosphorylation of Akt at Ser(473) in UVB-induced skin tumors. Together, our results indicate that honokiol holds promise for the prevention of UVB-induced skin cancer by targeting inflammatory mediators, cell cycle regulators and cell survival signals in UVB-exposed skin.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Mudit
authors.initials: M
authors.lastname: Vaid
authors.forename: Som D
authors.initials: SD
authors.lastname: Sharma
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Katiyar
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004365:Drugs, Chinese Herbal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism* / Q000528:radiation effects; D017705:Lignans / Q000627:therapeutic use*; D031566:Magnolia / Q000737:chemistry*; D051379:Mice; D008812:Mice, Hairless; D010212:Papilloma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000890:Anti-Infective Agents; D001713:Biphenyl Compounds; D018844:Cyclin-Dependent Kinases; D051546:Cyclooxygenase 2; D004365:Drugs, Chinese Herbal; D018836:Inflammation Mediators; D017705:Lignans; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols