Evaluation of the anti-melanoma action of sesquiterpenes isolated from a traditional Chinese medicinal herb Atractylodis Macrocephalae Rhizoma

Melanoma incidence is increasing rapidly, yet currently there is no effective treatment for late stage melanoma. The constitutively activated Ras/Erk and PI3K/Akt pathways have been implicated in the pathogenesis of melanoma, and parallel inhibition of the two pathways has been suggested to be a good approach for treating this malignancy. The traditional Chinese medicinal herb Atractylodis Macrocephalae Rhizoma (Baizhu in Chinese), the dried rhizome of Atractylodes macrocephala, is commonly prescribed by Chinese medicine practitioners for melanoma treatment; however the active constituent(s) and mechanism of action of Baizhu in treating melanoma are unknown. The fact that many naturally occurring sesquiterpenes have anti-melanoma effects, and that sesquiterpenes from Baizhu exert anticancer activities, including beneficial effects in cachectic cancer patients, encouraged us to isolate sesquiterpenes and screen them for their anti-melanoma effects. Our results have shown that, among 8 sesquiterpenes isolated from Baizhu, atractylenolide-I (AT-I) and AT-II can inhibit cell proliferation and migration, and induce apoptosis in murine B16 melanoma cells. These effects correlate with a remarkable inhibitory effect on Erk and Akt activity. Our recent data have also demonstrated that in human Hs 294T melanoma cells both compounds inhibit cell proliferation in a dose-dependent manner at 48 h with IC50 values of 24 μM for AT-I and 28 μM for AT-II, and markedly suppress the phosphorylation of Erk and Akt at a similar concentration. Moreover the two compounds demonstrated very low cytotoxicity in primary human epidermal keratinocytes. The objectives of this project are (1) to test the hypothesis that AT-I and AT-II inhibit cell proliferation, migration and adhesion, as well as induce apoptosis on multiple melanoma cell lines; (2) to test the hypothesis that AT-I and AT-II suppress Erk and Akt activities through modulating their upstream signaling components; and (3) to determine the tumor-suppressive efficacy and potential toxicity of AT-I in animals. The outcome of this study is expected to advance our understanding of the mode and mechanism of action of the two sesquiterpenes in melanoma and provide a chemical and pharmacological basis for the clinical application of Baizhu in melanoma management. This contribution will be significant because it is the first step in a continuum of research that is expected to lead to future clinical trials of the two sesquiterpenes and their potential derivatives as chemopreventive agents for melanoma. If successful, these efforts should lead to decreases in mortality from melanoma and in its associated costs.