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

Nuha Mahmoud1, Mohamed E M Saeed1, Yoshikazu Sugimoto2

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

Oncotarget
|December 6, 2018
PubMed

Insights

Nimbolide shows enhanced anticancer activity in cells overexpressing P-glycoprotein (ABCB1/MDR1), mediated by PTEN upregulation. This natural product also targets key metabolic regulators like HIF1α, suggesting potential in targeted cancer therapy.

Area of Science:

  • Natural product chemistry
  • Cancer biology
  • Molecular pharmacology

Background:

  • Nimbolide is a promising natural product for cancer treatment.
  • Mechanisms of multidrug resistance (MDR) can impact anticancer drug efficacy.
  • Understanding nimbolide's interaction with MDR is crucial for its therapeutic application.

Purpose of the Study:

  • To investigate the influence of known multidrug resistance (MDR) mechanisms on nimbolide's anticancer activity.
  • To identify molecular determinants of tumor cellular response to nimbolide.
  • To explore nimbolide's potential in targeted cancer therapy.

Main Methods:

  • Evaluation of nimbolide against cell lines with known MDR mechanisms (ABCB1, ABCG2, ABCB5, TP53, EGFR).
  • Analysis of gene expression changes (mRNA and protein) in response to nimbolide treatment.
  • COMPARE and hierarchical cluster analyses of transcriptome-wide microarray data from the NCI 60 cell line panel.

Main Results:

  • Hypersensitivity to nimbolide was observed in P-glycoprotein (ABCB1/MDR1)-overexpressing cells, linked to PTEN upregulation and ABCB1/MDR1 downregulation.
  • Nimbolide targeted metabolic regulators including HIF1α, FoxO1, and MYC, and affected reactive oxygen species.
  • Expression of ABCG2, EGFR, and mutant TP53 did not correlate with nimbolide's activity.
  • NF-κB was identified as a master regulator, and HIF1α as a mediator of nimbolide sensitivity.

Conclusions:

  • Nimbolide's efficacy is influenced by specific MDR mechanisms, particularly P-glycoprotein.
  • Nimbolide exhibits a multifaceted mechanism of action, targeting cellular metabolism and key regulatory pathways.
  • HIF1α's role in mediating nimbolide sensitivity highlights its potential for targeted cancer therapy.
Keywords:
HIF1αMDRNF-κBlimonoidsreactive oxygen species

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