Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation

Abstract

Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (<i>ABCB1</i>, <i>ABCG2</i>, <i>ABCB</i>5, <i>TP53</i>, <i>EGFR</i>) were evaluated against nimbolide. The P-glycoprotein (<i>ABCB1</i>/<i>MDR1</i>)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in <i>ABCB1</i>/<i>MDR1</i> mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor <i>TP53</i> did not correlate to nimbolide's activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide's activity. Interestingly, <i>HIF1α</i> was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.