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CELLULAR AND MOLECULAR

A Novel Benzodiazepine Selectively Inhibits Keratinocyte Proliferation and Reduces Retinoid-Induced Epidermal Hyperplasia in Organ-Cultured Human Skin

Departments of Pathology (J.V., N.B., K.C.N., H.S., K.F., K.J.), Chemistry (A.E.B., G.D.G.), Dermatology (S.K.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan

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.

Address correspondence to: Dr. James Varani, Department of Pathology, The University of Michigan, 1301 Catherine Rd./Box 0602, Ann Arbor, MI 48109. E-mail: varani{at}umich.edu

This article has been cited by other articles:

				N. Bhagavathula, K. C. Nerusu, A. Hanosh, M. N. Aslam, T. B. Sundberg, A. W. Opipari Jr., K. Johnson, S. Kang, G. D. Glick, and J. Varani 7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(naphthalen-2-ylmethyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (Bz-423), a Benzodiazepine, Suppresses Keratinocyte Proliferation and Has Antipsoriatic Activity in the Human Skin-Severe, Combined Immunodeficient Mouse Transplant Model J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 938 - 947. [Abstract] [Full Text] [PDF]