Exploring the involvement of Hsp90 signaling in the anti-melanoma effects of Flos Chrysanthemi and parthenolide

Malignant melanoma is highly aggressive. Inhibition of heat shock protein 90 (Hsp90) can lead to degradation of its client proteins thereby blocking their signaling pathways that are responsible for cancer progression. Inhibiting Hsp90 is a good strategy for treating melanoma. Juhua (Flos Chrysanthemi) is commonly prescribed for treating melanoma. It is reported that Juhua and its active component parthenolide possess anti-cancer activities. However, the underlying mechanisms of action of them are not fully understood. Our preliminary studies showed that Juhua and parthenolide exerted anti-melanoma effects in cultured cells and mice. Mechanistic studies showed that Juhua and parthenolide dose-dependently reduced ATPase activity of Hsp90α (the major isoform of Hsp90) and lowered levels of some Hsp90 client proteins in melanoma cells. We, therefore, hypothesize that inhibiting Hsp90 signaling is one of the mechanisms underlying the anti-melanoma effects of Juhua and parthenolide. To prove this hypothesis, we propose: 1) to further determine the anti-melanoma effects of Juhua and parthenolide in more cellular and animal models; 2) to determine how Hsp90 signaling is inhibited by Juhua and parthenolide; and 3) to determine whether inhibiting Hsp90 contributes to the anti-melanoma effects of Juhua and parthenolide. Results of this study will provide chemical and pharmacological justifications for the clinical application of Juhua in melanoma management and lay the groundwork for developing Juhua and parthenolide as novel anti-melanoma agents.