The role of oxidative stress has been tested in an animal model of UV-induced carcinogenesis. Identification of small molecule interventions that block solar UV-induced skin cancer by activating the NRF2 antioxidant response pathway as a cytoprotective adaptive response of human skin to solar exposure.
Georg Wondrak, PhD.
Donna Zhang, PhD.
- Solar exposure-induced skin pathology identified the role of oxidativestress in an animal ,odel of UV-induced carcinogenesis.
- This lead to the identification of small molecule inventions that block solar UV-induced skin cancer by activating the NRF2 antioxidant response pathway as a cytoprotective adaptive response of human skin to solar exposure.
- Pharmacological induction of oxidative and proteotoxic stress has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells.
- Guided by a differential phenotypic drug screen for novel lead compounds that selectively induce melanoma cell apoptosis without compromising viability of primary human melanocytes, we have focused on the cyclic pyridinyl-polythiazolyl peptide-antimicrobial thiostrepton.
- Using comparative gene expression-array analysis, the early cellular stress response induced by thiostrepton was examined in human A375 metastatic melanoma cells and primary melanocytes.
- Thiostrepton rapidly induced cellular oxidative stress followed by inactivation of chymotrypsin-like proteasomal activity and melanoma cell-directed accumulation of ubiquitinated proteins, not observed in melanocytes that were resistant to thiostrepton-induced apoptosis.
- Proteotoxic and apoptogenic effects were fully antagonized by antioxidant intervention.
- Our findings demonstrate that thiostrepton displays dual activity as a selective prooxidant and proteotoxic chemotherapeutic, suggesting feasibility of experimental intervention targeting metastatic melanoma and other malignancies including multiple myeloma.