Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer

András Füredi, Kornélia Szebényi, Szilárd Tóth, Mihály Cserepes, Lilla Hámori, Veronika Nagy, Edina Karai, Péter Vajdovich, T. Imre, P. Szabó, D. Szüts, J. Tóvári, G. Szakács

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)287-296
Number of pages10
JournalJournal of Controlled Release
Volume261
DOIs
Publication statusPublished - Sep 10 2017

Fingerprint

Drug Resistance
Breast Neoplasms
Doxorubicin
Multiple Drug Resistance
B-Cell Leukemia
Therapeutics
Survival
P-Glycoprotein
liposomal doxorubicin
1-dodecylpyridoxal
Allografts
Pharmacokinetics
Recurrence
Neoplasms

Keywords

  • Breast cancer
  • Genetically engineered mouse model
  • Multidrug resistance
  • P-glycoprotein
  • Pegylated liposomal doxorubicin

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer. / Füredi, András; Szebényi, Kornélia; Tóth, Szilárd; Cserepes, Mihály; Hámori, Lilla; Nagy, Veronika; Karai, Edina; Vajdovich, Péter; Imre, T.; Szabó, P.; Szüts, D.; Tóvári, J.; Szakács, G.

In: Journal of Controlled Release, Vol. 261, 10.09.2017, p. 287-296.

Research output: Contribution to journalArticle

Füredi, András ; Szebényi, Kornélia ; Tóth, Szilárd ; Cserepes, Mihály ; Hámori, Lilla ; Nagy, Veronika ; Karai, Edina ; Vajdovich, Péter ; Imre, T. ; Szabó, P. ; Szüts, D. ; Tóvári, J. ; Szakács, G. / Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer. In: Journal of Controlled Release. 2017 ; Vol. 261. pp. 287-296.
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