Malignant melanoma is an aggressive tumor of the skin and still lacks effective preventive and therapeutic treatments. In melanoma, both the BRAF/MEK/ERK and PI3-K/AKT signaling pathways are constitutively activated through multiple mechanisms, which result in cell-cycle progression and prevention of apoptosis. Therefore, the development of novel strategies for targeting BRAF and PI3K are of utmost importance. In this study, we found that Ashitaba (Angelica keiskei) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma development by directly targeting both BRAFV600E and PI3K, which blocked the activation of downstream signaling. This led to the induction of G1 phase cell-cycle arrest and apoptosis in melanoma cells. Importantly, 4HD or XAG dramatically attenuated tumor incidence and volume in the BRAF-activated Pten-deficient melanoma mouse model. Our findings suggest that 4HD and XAG are promising chemopreventive or potential therapeutic agents against melanomagenesis that act by targeting both BRAF and PI3K, providing hope for rapid clinical translation.
Bibliographical noteFunding Information:
The authors thank Tara Adams for supporting animal experiments, Todd Schuster for supporting experiments and Dr. Tia Rai for assistance in submitting this manuscript (The Hormel Institute, University of Minnesota, Austin, MN). This work was supported by The Hormel Foundation, NIH grants CA166011, CA187027, and CA196639 (to Z. Dong) and a National Natural Science Foundation of China, "Foreign Young Scientist" grant, NSFC81650110530 (to M. Fredimoses).
© 2018 American Association for Cancer Research.
Copyright 2018 Elsevier B.V., All rights reserved.
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural