Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1

Pharmacogenomics J. 2005;5(2):112-25. doi: 10.1038/sj.tpj.6500297.


To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI-National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations-indicative of MDR1-mediated resistance-were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Algorithms
  • Antineoplastic Agents, Phytogenic / metabolism*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Survival / drug effects
  • Cluster Analysis
  • DNA Probes
  • Databases, Factual
  • Down-Regulation / drug effects
  • Ellipticines / metabolism*
  • Ellipticines / pharmacology*
  • Flow Cytometry
  • Fluorescent Dyes
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, MDR / genetics*
  • Humans
  • Medical Informatics
  • Paclitaxel / toxicity
  • Principal Component Analysis
  • RNA, Small Interfering / genetics
  • Reproducibility of Results
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • DNA Probes
  • Ellipticines
  • Fluorescent Dyes
  • RNA, Small Interfering
  • Paclitaxel