8-Cl-Adenosine enhances 1,25-dihydroxyvitamin D3-induced growth inhibition without affecting 1,25-dihydroxyvitamin D3-stimulated differentiation of primary mouse epidermal keratinocytes.

Hdl Handle:
http://hdl.handle.net/10675.2/124
Title:
8-Cl-Adenosine enhances 1,25-dihydroxyvitamin D3-induced growth inhibition without affecting 1,25-dihydroxyvitamin D3-stimulated differentiation of primary mouse epidermal keratinocytes.
Authors:
Bollag, Wendy B; Zhong, Xiaofeng; Josephson, Sarah
Abstract:
BACKGROUND: Epidermal keratinocytes continuously proliferate and differentiate to form the mechanical and water permeability barrier that makes terrestrial life possible. In certain skin diseases, these processes become dysregulated, resulting in abnormal barrier formation. In particular, skin diseases such as psoriasis, actinic keratosis and basal and squamous cell carcinomas are characterized by hyperproliferation and aberrant or absent differentiation of epidermal keratinocytes. We previously demonstrated that 8-Cl-adenosine (8-Cl-Ado) can induce keratinocyte growth arrest without inducing differentiation. RESULTS: To determine if this agent might be useful in treating hyperproliferative skin disorders, we investigated whether 8-Cl-Ado could enhance the ability of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a known keratinocyte differentiating agent and a clinical treatment for psoriasis, to inhibit keratinocyte growth. We found that low concentrations of 8-Cl-Ado and 1,25(OH)2D3 appeared to act additively to reduce proliferation of primary mouse epidermal keratinocytes. However, another agent (transforming growth factor-beta) that triggers growth arrest without inducing differentiation also coincidentally inhibits differentiation elicited by other agents; inhibition of differentiation is suboptimal for treating skin disorders, as differentiation is often already reduced. Thus, we determined whether 8-Cl-Ado also decreased keratinocyte differentiation induced by 1,25(OH)2D3, as measured using the early and late differentiation markers, keratin 1 protein levels and transglutaminase activity, respectively. 8-Cl-Ado did not affect 1,25(OH)2D3-stimulated keratin 1 protein expression or transglutaminase activity. CONCLUSIONS: Our results suggest that 8-Cl-Ado might be useful in combination with differentiating agents for the treatment of hyperproliferative disorders of the skin.
Citation:
BMC Pharmacol. 2004 Jul 27; 4:13
Issue Date:
10-Aug-2004
URI:
http://hdl.handle.net/10675.2/124
DOI:
10.1186/1471-2210-4-13
PubMed ID:
15279680
PubMed Central ID:
PMC509244
Type:
Journal Article
ISSN:
1471-2210
Appears in Collections:
Department of Medicine Faculty: Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorBollag, Wendy Ben_US
dc.contributor.authorZhong, Xiaofengen_US
dc.contributor.authorJosephson, Sarahen_US
dc.date.accessioned2010-09-24T22:03:24Z-
dc.date.available2010-09-24T22:03:24Z-
dc.date.issued2004-08-10en_US
dc.identifier.citationBMC Pharmacol. 2004 Jul 27; 4:13en_US
dc.identifier.issn1471-2210en_US
dc.identifier.pmid15279680en_US
dc.identifier.doi10.1186/1471-2210-4-13en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/124-
dc.description.abstractBACKGROUND: Epidermal keratinocytes continuously proliferate and differentiate to form the mechanical and water permeability barrier that makes terrestrial life possible. In certain skin diseases, these processes become dysregulated, resulting in abnormal barrier formation. In particular, skin diseases such as psoriasis, actinic keratosis and basal and squamous cell carcinomas are characterized by hyperproliferation and aberrant or absent differentiation of epidermal keratinocytes. We previously demonstrated that 8-Cl-adenosine (8-Cl-Ado) can induce keratinocyte growth arrest without inducing differentiation. RESULTS: To determine if this agent might be useful in treating hyperproliferative skin disorders, we investigated whether 8-Cl-Ado could enhance the ability of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a known keratinocyte differentiating agent and a clinical treatment for psoriasis, to inhibit keratinocyte growth. We found that low concentrations of 8-Cl-Ado and 1,25(OH)2D3 appeared to act additively to reduce proliferation of primary mouse epidermal keratinocytes. However, another agent (transforming growth factor-beta) that triggers growth arrest without inducing differentiation also coincidentally inhibits differentiation elicited by other agents; inhibition of differentiation is suboptimal for treating skin disorders, as differentiation is often already reduced. Thus, we determined whether 8-Cl-Ado also decreased keratinocyte differentiation induced by 1,25(OH)2D3, as measured using the early and late differentiation markers, keratin 1 protein levels and transglutaminase activity, respectively. 8-Cl-Ado did not affect 1,25(OH)2D3-stimulated keratin 1 protein expression or transglutaminase activity. CONCLUSIONS: Our results suggest that 8-Cl-Ado might be useful in combination with differentiating agents for the treatment of hyperproliferative disorders of the skin.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.mesh2-Chloroadenosine / analogs & derivatives / pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCalcitriol / pharmacologyen_US
dc.subject.meshCell Differentiation / drug effectsen_US
dc.subject.meshCell Proliferation / drug effectsen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshDNA / biosynthesisen_US
dc.subject.meshDermatologic Agents / pharmacologyen_US
dc.subject.meshDrug Interactionsen_US
dc.subject.meshKeratin-1en_US
dc.subject.meshKeratinocytes / cytology / drug effects / metabolismen_US
dc.subject.meshKeratins / biosynthesisen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred ICRen_US
dc.subject.meshTransglutaminases / metabolismen_US
dc.title8-Cl-Adenosine enhances 1,25-dihydroxyvitamin D3-induced growth inhibition without affecting 1,25-dihydroxyvitamin D3-stimulated differentiation of primary mouse epidermal keratinocytes.en_US
dc.typeJournal Articleen_US
dc.identifier.pmcidPMC509244en_US
dc.contributor.corporatenameDepartment of Medicineen_US
dc.contributor.corporatenameDepartment of Cellular Biology and Anatomyen_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Geneticsen_US
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