Pharmacogenomic
Characterization of Cytotoxic Compounds
from <i>Salvia officinalis</i> in Cancer Cells
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Abstract
<i>Salvia officinalis</i> is used as a dietary supplement
with diverse medicinal activity (e.g. antidiabetic and antiatherosclerotic
effects). The plant also exerts profound cytotoxicity toward cancer
cells. Here, we investigated possible modes of action to explain its
activity toward drug-resistant tumor cells. Log<sub>10</sub>IC<sub>50</sub> values of two constituents of <i>S. officinalis</i> (ursolic acid, pomolic acid) were correlated to the expression of
ATP-binding cassette (ABC) transporters (P-glycoprotein/<i>ABCB1/MDR1</i>, MRP1/<i>ABCC1</i>, BCRP/<i>ABCG2</i>) and epidermal
growth factor receptor (<i>EGFR</i>) or mutations in <i>RAS</i> oncogenes and the tumor suppressor gene <i>TP53</i> of the NCI panel of cell lines. Gene expression profiles predicting
sensitivity and resistance of tumor cells to these compounds were
determined by microarray-based mRNA expressions, COMPARE, and hierarchical
cluster analyses. Furthermore, the binding of both plant acids to
key molecules of the NF-κB pathway (NF-κB, I-κB,
NEMO) was analyzed by molecular docking. Neither expression nor mutation
of ABC transporters, oncogenes, or tumor suppressor genes correlated
with log<sub>10</sub>IC<sub>50</sub> values for ursolic acid or pomolic
acid. In microarray analyses, many genes involved in signal transduction
processes correlated with cellular responsiveness to these compounds.
Molecular docking indicated that the two plant acids strongly bound
to target proteins of the NF-κB pathway with even lower free
binding energies than the known NF-κB inhibitor MG-132. They
interacted more strongly with DNA-bound NF-κB than free NF-κB,
pointing to inhibition of DNA binding by these compounds. In conclusion,
the lack of cross-resistance to classical drug resistance mechanisms
(ABC-transporters, oncogenes, tumor suppressors) may indicate a promising
role of the both plant acids for cancer chemotherapy. Genes involved
in signal transduction may contribute to the sensitivity or resistance
of tumor cells to ursolic and pomolic acids. Ursolic and pomolic acid
may target different steps of the NF-κB pathway to inhibit NF-κB-mediated
functions