Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer
Abstract
Success of cancer treatment is often hampered by the emergence of multidrug resistance (MDR) mediated by P-glycoprotein (ABCB1/Pgp). Doxorubicin (DOX) is recognized by Pgp and therefore it can induce therapy resistance in breast cancer patients. In this study our aim was to evaluate the susceptibility of the pegylated liposomal formulation of doxorubicin (PLD/Doxil®/Caelyx®) to MDR. We show that cells selected to be resistant to DOX are cross-resistant to PLD and PLD is also ineffective in an allograft model of doxorubicin-resistant mouse B-cell leukemia. In contrast, PLD was far more efficient than DOX as reflected by a significant increase of both relapse-free and overall survival of Brca1-/-;p53-/- mammary tumor bearing mice. Increased survival could be explained by the delayed onset of drug resistance. Consistent with the higher Pgp levels needed to confer resistance, PLD administration was able to overcome doxorubicin insensitivity of the mouse mammary tumors. Our results indicate that the favorable pharmacokinetics achieved with PLD can effectively overcome Pgp-mediated resistance, suggesting that PLD therapy could be a promising strategy for the treatment of therapy-resistant breast cancer patients.
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Blocking ABCG2-mediated drug efflux by inhibiting ABCG2 expression could efficiently reverse multidrug resistance and enhance the sensitivity of cancer cells to chemotherapeutics.
“Therefore, to block ABCG2-mediated drug efflux by inhibiting the ABCG2 expression could efficiently reverse MDR in the carcinogenesis and enhance the sensitivity of cancer cells to chemotherapeutics.14”
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Liang, X., Wang, Y., Shi, H., Dong, M., Han, H., & Li, Q. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s304526 · Cited by 41 · see citing works
- Authors
- Füredi, A., Szebényi, K., Tóth, S., Cserepes, M., Hámori, L., Nagy, V., Karai, E., Vajdovich, P., Imre, T., Szabó, P., Szüts, D., Tóvári, J., & Szakács, G.
- Affiliations
- Institute of Molecular Life Sciences (HU)
- Medical University of Vienna (AT)
- National Institute of Oncology (HU)
- Magyar Agrár- és Élettudományi Egyetem (HU)
- Corresponding author
- Szakács, Gergely
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 261
- Pages
- 287-296
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2733703420
- Cited by
- 100
- References
- 83
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 10 · 2023: 13 · 2022: 14 · 2021: 10 · 2020: 16 · 2019: 11 · 2018: 4 · 2017: 2
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- Funders
- Hungarian Academy of Sciences (LP-2010-003/2015)
- ERC (260572)
- Austrian Science Fund (SFB35)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- pegylated liposomal doxorubicin, doxorubicin resistance, multidrug resistance, P-glycoprotein, breast cancer, drug resistance reversal, BRCA1, p53, mammary tumors, B-cell leukemia, pharmacokinetics, genetically engineered mouse models
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Doxorubicin, Female, Humans, Male, Mammary Neoplasms, Experimental, Polyethylene Glycols, Leukemia, B-Cell, Survival Rate, Mice, Knockout, Drug Resistance, Multiple, Disease-Free Survival, Drug Resistance, Neoplasm, ATP Binding Cassette Transporter, Subfamily B, Member 1, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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