Received for publication September 5, 2007.
Revised November 28, 2007.
Accepted for publication November 28, 2007.

Bz-423, a Benzodiazepine, Suppresses Keratinocyte Proliferation and has Anti-Psoriatic Activity in the Human Skin-SCID Mouse Transplant Model

Abstract

Bz-423 is a benzodiazepine that has cytotoxic and cytostatic activity against a variety of cells in vivo and in vitro. In the present study we demonstrate that Bz-423 (formulated for topical delivery) reduces epidermal hyperplasia in human psoriatic skin after transplantation to severe, combined immuno-deficient mice. Bz-423 also suppresses the hyperplasia that develops in non-psoriatic human skin as a consequence of transplantation to scid mice. Proliferation of human epidermal keratinocytes in monolayer culture was suppressed by Bz-423 at concentrations of 0.5-2.0 µM; concentrations below which cytotoxicity was detected. Keratinocyte growth arrest was accompanied by redistribution of -catenin from a cytoplasmic pool to the cell membrane and by reduced levels of c-myc, and cyclin D1 (two molecules associated with growth-inhibition via Wnt pathway signaling). Several analogues of Bz-423 were examined for anti-proliferative activity against human epidermal keratinocytes and human fibroblasts in monolayer culture. Each of the analogues tested suppressed growth of both cell types, but in all cases, keratinocytes were more sensitive than fibroblasts. Two of the compounds that were most selective for keratinocytes were found to suppress epidermal hyperplasia induced with all-trans retinoic acid in organ cultures of human skin. Taken together, these data show that Bz-423 and certain analogues produce biological responses in skin cells in vitro and in vivo which are consistent with therapeutic goals for treating psoriasis or epidermal hyperplasia resulting from other causes.

Key words: benzodiazepines, growth-suppression, hyperplasia, keratinocytes, organ culture, psoriasis