UC Berkeley

Natural products have been used for their medicinal properties throughout history, from ancient Mesopotamia to modern day herbal medicine. It is also estimated that 60% of currently available drugs are derived, either directly or indirectly, from natural products. Natural phytochemicals have been shown to exert strong anti-cancer, anti-obesity, and anti-bacterial effects as well as play a protective role against inflammation in the body and the brain. Due to their pleiotropic effects, these natural compounds have tremendous potential for treatment in diseases, such as melanoma and traumatic brain injury, where the heterogeneity within the tumor and among patients, respectively, has been shown to impede the development of new pharmacological agents for treatment. Melanoma, accounting for 3% of all skin cancers, but responsible for 65% of all skin-cancer related deaths, represents a great burden continuously on the rise. Current treatment options for metastatic melanoma offer short-term reprieve as resistance, due to intratumor heterogeneity, occurs within several months. Therefore, identification of a compound that can inhibit cell proliferation, regardless of the phenotype, is of dire need. Here, we show the anti-proliferative effects of 3’3-diindolylmethane (DIM), a bioactive compound found in cruciferous vegetables, on a diverse selection of melanoma cell lines. DIM inhibits cell growth in all treated melanoma cells through the down-regulation of the “master-regulator” of melanoma biology, the transcription factor, MITF-M. Due to its low toxicity, combining DIM with already established direct target therapies, could help patients overcome tumor heterogeneity driven- resistance without the deleterious effects of “cocktail-mixing”. We also describe for the first time a novel activator of the inwardly-rectifying potassium channel, Kir7.1. Progesterone, known for its positive effects following traumatic brain injury, was shown to potentiate Kir7.1 current in multiple cell types, including choroid plexus epithelial cells, in a G-protein independent manner. We found this progesterone-induced activation of Kir7.1 was inhibited in the presence of 20μM ursolic acid. Here, we describe for the first time an endogenous activator and natural phytochemical inhibitor of the Kir7.1, a vital ion channel in mammalian physiology.