Abstract
We have found previously that acquired doxorubicin resistance in a genetically engineered mouse model for BRCA1-related breast cancer was associated with increased expression of the mouse multidrug resistance (Mdr1) genes, which encode the drug efflux transporter ATP-binding cassette B1/P-glycoprotein (P-gp). Here, we show that even moderate increases of Mdr1 expression (as low as 5-fold) are sufficient to cause doxorubicin resistance. These moderately elevated tumor P-gp levels are below those found in some normal tissues, such as the gut. The resistant phenotype could be completely reversed by the third-generation P-gp inhibitor tariquidar, which provides a useful strategy to circumvent this type of acquired doxorubicin resistance. The presence of MDR1A in drug-resistant tumors with a moderate increase in Mdr1a transcripts could be shown with a newly generated chicken antibody against a mouse P-gp peptide. Our data show the usefulness of realistic preclinical models to characterize levels of Mdr1 gene expression that are sufficient to cause resistance.
Highlights
The anthracycline doxorubicin is frequently used in standard adjuvant, neoadjuvant, or palliative chemotherapy regimens for breast cancer patients [1]
Doxorubicin resistance of Brca1À/À;p53À/À tumors with a moderate increase of Mdr1a/Mdr1b expression can be reversed by the P-gp inhibitor tariquidar
In addition to www.aacrjournals.org published ratios of resistant tumors versus matched samples taken before treatment [2], we determined Mdr1 gene expression levels in doxorubicin-sensitive and doxorubicin-resistant mouse mammary tumors in comparison with selected normal tissues by reverse transcription-Multiplex ligationdependent probe amplification (MLPA). actinb, hypoxanthine phosphoribosyltransferase 1 (Hprt1), and b2-microglobulin were used as reference and relative Mdr1 transcript levels were compared with those of the liver, gut, adrenals, and kidney, which are known to express P-gp
Summary
The anthracycline doxorubicin is frequently used in standard adjuvant, neoadjuvant, or palliative chemotherapy regimens for breast cancer patients [1]. Successful chemotherapy of breast cancer is hampered by the development of multidrug resistance. A range of different mechanisms has been identified, including alterations in drug target, drug accumulation/metabolism, DNA repair, or cell death pathways [3,4,5,6]. For several of these mechanisms, their relevance to resistance in real tumors is sparse [7,8,9,10].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.