According to the WHO, cancer is still a leading cause of morbidity and the second leading cause of death worldwide. The incidence of melanoma is rising faster than any other solid tumor type and melanoma are responsible for 79% of all skin cancer deaths. Especially at an advanced stage, melanoma is still one of the most aggressive and incurable types of cancer. Today, about 79% of all approved anti-cancer drugs are natural products or derived from them demonstrating their important role in medicine [1]. In a previous study, shikonin derivatives isolated from the roots of Onosma paniculata Bur. & Franch. (Boraginaceae) have emerged as interesting candidates for finding new drug leads against cancer [2]. We now prepared several novel semisynthetic shikonin derivatives and analyzed their cytotoxic potential against different melanoma cell lines. The most active compound was (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopropylacetate (CP). It was especially more active against two melanoma cell lines derived from metastatic lesions compared to the most active isolated derivative b - b -dimethylacrylshikonin (DMAS). IC50 values of CP and DMAS were 4.9 µM (WM164) and 3.2 µM (MUG-Mel-2), and 8.3 µM and 7.2 µM, respectively. Further investigations revealed that CP induced apoptosis, but did not lead to cell cycle arrest. Moreover, the ApoToxGlo® assay together with the LDH assay revealed that CP did not significantly damage the cell membrane up to 48h and 5.0 µM.
Acknowledgement: The Austrian Science Fund (FWF) is acknowledged for financial support (Project P27505).
References:
[1] Newman D. J., Cragg G. M (2016)
Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod 79(3): 629-661.
[2] Kretschmer N. Rinner B., Deutsch A.J., Lohberger B., Knausz H., Kunert O., Blunder M., Boechzelt H., Schaider H., Bauer R.(2012) Naphthoquinones from Onosma paniculata Induce Cell-Cycle Arrest and Apoptosis in Melanoma Cells. J Nat Prod, 75(5): 865-869.