Nordihydroguaiaretic acid-mediated inhibition of ultraviolet B-induced activator protein-1 activation in human keratinocytes.

Nordihydroguaiaretic acid (NDGA) is a polyphenolic compound from the Larrea tridentata bush that has been identified as a chemopreventive drug in animal studies. Topically applied NDGA has been shown to prevent phorbol ester promotion of tumors in mouse skin, suggesting that NDGA may be a candidate drug for the chemoprevention of skin cancer. Ultraviolet (UV) B irradiation from sunlight exposure is the major cause of human skin cancer. UVB irradiation causes epigenetic alterations in target keratinocytes, such as the upregulation of signal transduction pathways that induce the expression of transcription factors. Specifically, UVB induces activator protein-1 (AP-1), a transcription factor complex that alters normal cellular gene expression. A component of the UVB-induced AP-1 complex, c-fos, also was identified as a mediator of the signaling pathway that leads to AP-1 activation. Thus, NDGA was investigated as a potential inhibitory agent for UVB-induced signaling pathways in the human keratinocyte cell line HaCaT. NDGA significantly inhibited UVB-induced c-fos and AP-1 transactivation. In addition, NDGA was found to inhibit activity of phosphatidylinositol 3-kinase (PI 3-kinase), a UVB-inducible enzyme that contributes to the induced expression of c-fos and AP-1. Therefore, NDGA prevents UVB-induced c-fos expression and AP-1 transactivation by inhibiting the PI 3-kinase signaling pathway. Effective skin chemoprevention strategies may incorporate NDGA to inhibit components of the UVB-induced cell signaling pathways that increase AP-1 activity.