Camptothecin induces differentiation, tissue transglutaminase and apoptosis in cultured keratinocytes

Cultured normal human adult keratinocytes were exposed to (S)-(+)- camptothecin over the concentration range 10(-5) to 10(-10) M. The dose-dependent inhibition of growth was recorded using cell counting. The induction of terminal differentiation was demonstrated by the relative increase in squamous and cornified cells, and the concomitant decrease in small, proliferative cells, with an overall decrease in total cell numbers on going from 10(-10) to 10(-6) M concentration of the drug. The induction of apoptosis was studied by assay of two types of transglutaminase, "tissue" and "keratinocyte", and by assay of histone-linked mono- and oligonucleosomes. Induction of apoptosis was accompanied with increase in "tissue" transglutaminase and in the amount of nucleosomes, the latter being indicative of endonuclease activity. This activity was sharply increased at a camptothecin concentration of 10(-5) M, and may have been facilitated by "tissue" transglutaminase at lower concentrations. The data suggest that camptothecin restricts keratinocyte growth by several mechanisms including apoptosis and emphasize its possible use in topical therapy for psoriasis.