(-)-
Sesamin is a
lignan present in sesam oil and a number of medicinal plants. It exerts various pharmacological effects, such as prevention of
hyperlipidemia,
hypertension, and
carcinogenesis. Moreover, (-)-
sesamin has chemopreventive and anticancer activity in vitro and in vivo. Multidrug resistance (MDR) of
tumors leads to fatal treatment outcome in many patients and novel drugs able to kill multidrug-resistant cells are urgently needed.
P-glycoprotein (MDR1/ABCB1) is the best known
ATP-binding cassette (ABC)
drug transporter mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. We found that the
mRNA expressions of ABCB1 and ABCB5 were not related to the 50% inhibition concentrations (IC50) for (-)-
sesamin in a panel of 55 cell lines of the National Cancer Institute, USA. Furthermore, (-)-
sesamin inhibited ABCB1- or ABCB5-overexpressing cells with similar efficacy than their
drug-sensitive parental counterparts. In addition to
ABC transporter-mediated MDR, we attempted to identify other molecular determinants of (-)-
sesamin resistance. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based
mRNA expression of the NCI cell panel. Twenty-three genes were identified, whose
mRNA expression correlated with the IC50 values for (-)-
sesamin. These genes code for
proteins of different
biological functions, i.e.
ribosomal proteins, components of the mitochondrial respiratory chain,
proteins involved in
RNA metabolism, protein biosynthesis, or
glucose and
fatty acid metabolism. Subjecting this set of genes to cluster analysis showed that the cell lines were assembled in the resulting dendrogram according to their responsiveness to (-)-
sesamin. In conclusion, (-)-
sesamin is not involved in MDR mediated by ABCB1 or ABCB5 and may be valuable to bypass chemoresistance of refractory
tumors. The microarray expression profile, which predicted sensitivity or resistance of
tumor cells to (-)-
sesamin consisted of genes, which do not belong to the classical resistance mechanisms to established anticancer drugs.