Oncotarget

Research Papers:

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 and Thomas Efferth _

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Oncotarget. 2018; 9:35762-35779. https://doi.org/10.18632/oncotarget.26299

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Abstract

Nuha Mahmoud1, Mohamed E.M. Saeed1, Yoshikazu Sugimoto2, Sabine M. Klauck3, Henry J. Greten4,5 and Thomas Efferth1

1Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany

2Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan

3Division of Cancer Genome Research, German Cancer Research Center, German Cancer Consortium, National Center for Tumor Diseases, Heidelberg, Germany

4Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal

5Heidelberg School of Chinese Medicine, Heidelberg, Germany

Correspondence to:

Thomas Efferth, email: [email protected]

Keywords: HIF1α; limonoids; MDR; NF-κB; reactive oxygen species

Received: September 26, 2018     Accepted: October 24, 2018     Published: November 06, 2018

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.


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