TY - JOUR
T1 - Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines
AU - Huang, Rong
AU - Murry, Daryl J.
AU - Kolwankar, Dhanashri
AU - Hall, Stephen D.
AU - Foster, David R.
PY - 2006/6/14
Y1 - 2006/6/14
N2 - 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.
AB - 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.
KW - ABCB1
KW - ABCC1
KW - ABCC2
KW - ABCC3
KW - Transcriptional regulation
KW - Vincristine
UR - http://www.scopus.com/inward/record.url?scp=33646497418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646497418&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2006.03.009
DO - 10.1016/j.bcp.2006.03.009
M3 - Article
C2 - 16620787
AN - SCOPUS:33646497418
SN - 0006-2952
VL - 71
SP - 1695
EP - 1704
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 12
ER -