In vitro and in vivo reversal of MDR1-mediated multidrug resistance by KT-5720: Implications on hematological malignancies

Hanan Galski, Hamutal Sivan, Philip Lazarovici, Arnon Nagler

Research output: Contribution to journalArticlepeer-review

Abstract

Multidrug resistance (MDR) due to over-expression of the MDR1 (ABCB1) gene and its P-glycoprotein (Pgp) product is an obstacle in the treatment of hematological malignancies. In this study, we have evaluated the potency of KT-5720 to reverse Pgp-dependent MDR in vitro and in vivo. KT-5720 (but not its close derivatives, K252a and K252b) reversed multidrug resistance of LM1/MDR cell line at non-toxic concentrations and increased accumulation of rhodamine 123 (Rh123). KT-5720 significantly reversed MDR1-dependent resistance of primary malignant cells from patients with chronic myelogenous leukemia in blast crisis (CML-BC) and advanced multiple myeloma (MM). Moreover, KT-5720 (at 5 mg/kg) sensitized the bone marrow of MDR1 transgenic mice model towards daunorubicin (at 8 mg/kg) without general toxic effects. Therefore, KT-5720 can be considered as candidate for combination therapy in various hematological malignancies where Pgp activity is a major impediment for cure.

Original languageEnglish
Pages (from-to)1151-1158
Number of pages8
JournalLeukemia Research
Volume30
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

Keywords

  • CML-BC
  • KT-5720
  • Lymphoma
  • MDR1
  • Multiple myeloma (MM)
  • P-glycoprotein (Pgp)

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