A novel benzodiazepine selectively inhibits keratinocyte proliferation and reduces retinoid-induced epidermal hyperplasia in organ-cultured human skin.
Bz-423 is a new benzodiazepine that has cytotoxic and cytostatic effects against a number of cell types in culture, and recent studies have shown efficacy in experimental lupus models in rodents. The present study demonstrates that treating human skin in organ culture with Bz-423 suppresses retinoid-induced epidermal hyperplasia. Bz-423 suppresses hyperplasia in organ culture at concentrations that also inhibit keratinocyte proliferation in monolayer culture but that are not cytotoxic for keratinocytes and do not inhibit fibroblast growth. Under conditions in which keratinocyte proliferation is inhibited, there is no measurable effect on epidermal growth factor receptor activation, but there is reduced signaling at the level of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase. Suppression of keratinocyte growth by Bz-423 is associated with generation of intracellular oxidants. However, antioxidant treatment reduces keratinocyte cytotoxicity that occurs at high concentrations of Bz-423, but it does not inhibit growth suppression. Together, these data suggest that Bz-423 has the potential to limit the untoward effects associated with topical retinoid treatment, and in addition, may have therapeutic effects against other forms of epidermal hyperplasia.
Varani
James
J
Department of Pathology, The University of Michigan, 1301 Catherine Rd./Box 0602, Ann Arbor, MI 48109, USA. varani@umich.edu
Bhagavathula
Narasimharao
N
Nerusu
Kamalakar C
KC
Sherzer
Hilary
H
Fay
Kevin
K
Boitano
Anthony E
AE
Glick
Gary D
GD
Johnson
Kent
K
Kang
Sewon
S
Opipari
Anthony W
AW
D019898:Autocrine Communication / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D015151:Immunoblotting; D007202:Indicators and Reagents; D015603:Keratinocytes / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009924:Organ Culture Techniques; D019899:Paracrine Communication / Q000187:drug effects; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D012176:Retinoids / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology*
D007202:Indicators and Reagents; D017382:Reactive Oxygen Species; D012176:Retinoids; D001569:Benzodiazepines; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; C468549:Bz-423