Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines

Rong Huang, Daryl J. Murry, Dhanashri Kolwankar, Stephen D. Hall, David R. Foster

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58 Scopus citations

Abstract

The increased expression of drug transporters following cancer chemotherapy contributes to resistance. This may reflect transcriptional up-regulation and/or clonal selection. We quantified the expression of mRNA for ABCB1 (mdr1), ABCC1 (mrp1), ABCC2 (mrp2) and ABCC3 (mrp3) to evaluate the potential contribution of induction. ABCB1, ABCC1-3 mRNAs were quantified by real time RT-PCR and normalized to GAPDH. We used intestinal cells that express high pregnane X receptor (LS174T), low pregnane X receptor (Caco-2) and lung cells (A549) that express glucocorticoid receptor and low pregnane X receptor. Rifampin (10 μM) caused significant induction of ABCB1 (595 ± 263%, p < 0.05) in LS174T cells but induction was absent in Caco-2 or A549 cells. ABCC1 was not induced in any cell at 24, 48 and 72 h following rifampin treatment. In contrast, vincristine (10 nM and 100 nM), a ligand for ABCB1 and ABCC1-3 and a potential PXR/CAR ligand, induced ABCC2 and ABCC3 expression in LS174T cells at 48 h (372 ± 87% and 303 ± 42%, respectively, p < 0.05). A similar induction of ABCC2 and ABCC3 genes was also seen with 10 nM VCR in A549 cells following 48 h treatment. In summary, there may be a significant contribution of transcriptional activation to multi-drug resistance. However, this is cell selective and is not necessarily dependent on PXR mediated effects.

Original languageEnglish (US)
Pages (from-to)1695-1704
Number of pages10
JournalBiochemical Pharmacology
Volume71
Issue number12
DOIs
Publication statusPublished - Jun 14 2006

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Keywords

  • ABCB1
  • ABCC1
  • ABCC2
  • ABCC3
  • Transcriptional regulation
  • Vincristine

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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