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

Nuha Mahmoud, Mohamed E.M. Saeed, Yoshikazu Sugimoto, Sabine M. Klauck, Henry J. Greten, Thomas Efferth

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 (ABCB1, ABCG2, ABCB5, TP53, EGFR) were evaluated against nimbolide. The P-glycoprotein (ABCB1/MDR1)-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 ABCB1/MDR1 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 TP53 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, HIF1α was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.

Original languageEnglish
Pages (from-to)35762-35779
Number of pages18
JournalOncotarget
Volume9
Issue number87
Publication statusPublished - 2018 Nov 1

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Keywords

  • HIF1α
  • Limonoids
  • MDR
  • NF-κB
  • Reactive oxygen species

ASJC Scopus subject areas

  • Oncology

Cite this

Mahmoud, N., Saeed, M. E. M., Sugimoto, Y., Klauck, S. M., Greten, H. J., & Efferth, T. (2018). Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation. Oncotarget, 9(87), 35762-35779.