Currently, one in every three cancers diagnosed is a skin cancer. Melanoma accounts
for only 4% of all skin cancers but is responsible for ca. 79% of skin cancer deaths.
Moreover, the incidence of malignant melanoma is rising faster than any other solid
tumor type. Even though the survival rate is 100% at a very early stage, it drops
dramatically at an advanced stage and leaves melanoma then as one of the most aggressive
and incurable types of solid cancer. This reflects the need for the discovery and
development of new respective anti-cancer drugs. In a previous study [1], we discovered
that dimethylacrylshikonin, isolated from the roots of Onosma paniculata Bur.&Franch. (Boraginaceae), exhibited the lowest IC50 of several isolated shikonin derivatives and was most active towards melanoma cell
lines. Therefore, it was chosen for more in-depth investigations. We did a comprehensive
gene expression study using the metastatic melanoma cell line WM164. Cells were treated
with 8µM dimethylacrylshikonin for 24h and the gene expression signature was compared
to vehicle-treated control cells (vehicle: 0.5% DMSO). 1192 distinct mRNAs could be
identified as expressed in all three biological replicates out of which 89 were 2-fold
differentially expressed (n = 3). Testing for significantly differentially expressed
genes following the Benjamini-Hochberg correction for multiple testing resulted in
31 distinct mRNAs. The most interesting candidates (among other things sequestosome
1) are known to be involved in apoptosis, cell proliferation, survival and/or drug
resistance and were validated and confirmed by semi-quantitative real-time PCR. Additional
experiments are in progress to study the changes in different signaling pathways in
more detail to reveal the exact mode of action.
[1] Kretschmer et al, J Nat Prod, 2012, 75:865 – 9.