title: Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes.
abstract: Although the skin production of vitamin D is initiated by ultraviolet radiation type B (UVB), the role vitamin D plays in antioxidative or pro-oxidative responses remains to be elucidated. We have used immortalized human HaCaT keratinocytes as a model of proliferating epidermal cells to test the influence of vitamin D on cellular response to H2O2 or the anti-cancer drug, cisplatin. Incubation of keratinocytes with 1,25(OH)2D3 or its low calcemic analogues, 20(OH)D3, 21(OH)pD or calcipotriol, sensitized cells to ROS resulting in more potent inhibition of keratinocyte proliferation by H2O2 in the presence of vitamin D compounds. These results were supported by cell cycle and apoptosis analyses, and measurement of the mitochondrial transmembrane potentials (MMP), however some unique properties of individual secosteroids were observed. Furthermore, in HaCaT keratinocytes treated with H2O2, 1,25(OH)2D3, 21(OH)pD and calcipotriol stimulated the expression of SOD1 and CAT genes, but not SOD2, indicating a possible role of mitochondria in ROS-modulated cell death. 1,25(OH)2D3 also showed a short-term, protective effect on HaCaT keratinocytes, as exemplified by the inhibition of apoptosis and the maintenance of MMP. However, with prolonged incubation with H2O2 or cisplatin, 1,25(OH)2D3 caused an acceleration in the death of the keratinocytes. Therefore, we propose that lead vitamin D derivatives can protect the epidermis against neoplastic transformation secondary to oxidative or UV-induced stress through activation of vitamin D-signaling. Furthermore, our data suggest that treatment with low calcemic vitamin D analogues or the maintenance of optimal level of vitamin D by proper supplementation, can enhance the anticancer efficacy of cisplatin.
authors.affiliation: Department of Histology, Medical University of Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Piotrowska
authors.affiliation: Department of Histology, Medical University of Gdańsk, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Wierzbicka
authors.affiliation: Department of Histology, Medical University of Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Ślebioda
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Woźniak
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
authors.affiliation: Departments of Dermatology and Pathology, University of Alabama at Birmingham, USA; Birmingham VA Medical Center, Birmingham, AL 35294, USA.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
authors.affiliation: Department of Histology, Medical University of Gdańsk, Poland. Electronic address: mzmijewski@gumed.edu.pl.
authors.forename: Michał A
authors.initials: MA
authors.lastname: Żmijewski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D014807:Vitamin D; C055085:calcipotriene; D006861:Hydrogen Peroxide; D002117:Calcitriol; D002945:Cisplatin
keywords: Cisplatin; Keratinocytes; Oxidative stress; Reactive oxygen species; Vitamin D; Vitamin D analogues