Hematological malignancies frequently have a poor prognosis and often remain incurable. Drug resistance, severe side effects, and relapse are major problems of currently used drugs, and new candidate compounds are required for improvement of
therapy success. The
naphthoquinone shikonin derived from the Chinese medicinal herb, Lithospermum erythrorhizon, is a promising candidate for the next generation of
chemotherapy. The basal cellular mechanism of
shikonin is the direct targeting of mitochondria. Cytotoxicity screenings showed that the compound is particularly effective against
leukemia cells suggesting an additional cellular mechanism.
mRNA and
miRNA microarrays were used to analyze changes in gene expression in
leukemia cells after
shikonin treatment and combined with stable-
isotope dimethyl labeling for quantitative proteomics. The integration of bioinformatics and the three "-omics" assays showed that the PI3K-Akt-mTOR pathway was affected by
shikonin. Deregulations of this pathway are frequently associated with cancerogenesis, especially in a wide range of
hematological malignancies. The effect on the PI3K-Akt-mTOR axis was validated by demonstrating a decreased phosphorylation of Akt and a direct inhibition of the IGF1R
kinase activity after
shikonin treatment. Our results indicate that inhibiting the IGF1R-Akt-mTOR signaling cascade is a new cellular mechanism of
shikonin strengthening its potential for the treatment of
hematological malignancies.