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- Title
Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes.
- Authors
Calcagno, A. M.; Fostel, J. M.; To, K. K. W.; Salcido, C. D.; Martin, S. E.; Chewning, K. J.; Wu, C.-P.; Varticovski, L.; Bates, S. E.; Caplen, N. J.; Ambudkar, S. V.
- Abstract
Understanding the mechanisms of multidrug resistance (MDR) could improve clinical drug efficacy. Multidrug resistance is associated with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clinically relevant drug concentrations are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concentrations reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 nM doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference analysis confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter association, indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.
- Subjects
DOXORUBICIN; CANCER cells; GENETIC regulation; DRUG efficacy; EPIGENESIS; MESSENGER RNA; COLON cancer; RNA metabolism; PROTEIN metabolism; ANTINEOPLASTIC antibiotics; COLON tumors; BIOCHEMISTRY; PROTEINS; REVERSE transcriptase polymerase chain reaction; OVARIAN tumors; MITOXANTRONE; WESTERN immunoblotting; ANTINEOPLASTIC agents; RNA; METABOLISM; DRUG resistance; PHENOMENOLOGY; GENES; RESEARCH funding; TUMORS; POLYMERASE chain reaction; CELL lines; CARRIER proteins; BREAST tumors; DRUG resistance in cancer cells; PHARMACODYNAMICS
- Publication
British Journal of Cancer, 2008, Vol 98, Issue 9, p1515
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/sj.bjc.6604334