Teriflunomide encourages cytostatic and apoptotic effects in premalignant and malignant cutaneous keratinocytes

Teriflunomide (TFN) reportedly inhibits de novo pyrimidine synthesis and exhibits anti-inflammatory, disease-modifying activities in vivo. These qualities would suggest that TFN could be useful in skin cancer chemoprevention or therapy. We investigated some mechanistic aspects of this tenet by characterizing the effects of TFN on premalignant and malignant human cutaneous keratinocytes. TFN promoted a dose- and/or time-dependent cytostasis and in these cells, which was followed by apoptosis. These features occurred in the presence of a physiological concentration of uridine in the culture medium. The short-term S phase arrest triggered by TFN was reversible in the malignant keratinocytes, and the indirect apoptosis induction was apparently preceded by mitochondrial disruption and reactive oxygen species production in both the premalignant and malignant keratinocytes. Respiration deficient malignant keratinocytes were resistant to the acute cytostatic and latent apoptotic effects of TFN implicating de novo pyrimidine synthesis and mitochondrial bioenergetics as the primary targets for TFN in the respiring cells. These novel mechanistic findings support a role for TFN in skin cancer chemoprevention and therapy.