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Combination of Elacridar with Imatinib Modulates Resistance Associated with Drug Efflux Transporters in Chronic

Raquel Alves1,2,3, Ana Cristina Gonçalves1,2,3, Joana Jorge1,2,3

  • 1Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal.

Biomedicines
|May 28, 2022
PubMed

Insights

Elacridar combined with imatinib overcomes imatinib resistance in chronic myeloid leukemia (CML) by re-sensitizing cells. This combination therapy induces apoptosis and reduces proliferation, offering a potential new treatment for TKI-resistant CML.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Multidrug resistance (MDR) compromises chemotherapy efficacy, particularly in chronic myeloid leukemia (CML).
  • Imatinib resistance in CML is linked to BCR-ABL1 alterations and altered drug efflux mediated by SLC and ABC transporters.
  • P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are key efflux transporters implicated in CML drug resistance.

Purpose of the Study:

  • To evaluate the therapeutic potential of elacridar, a P-gp and BCRP inhibitor, in CML.
  • To assess elacridar's efficacy as monotherapy and in combination with imatinib against imatinib-sensitive and resistant CML cell lines.
  • To investigate the mechanisms underlying elacridar's effects on CML cell viability, proliferation, and apoptosis.

Main Methods:

  • Utilized sensitive (K562, LAMA-84) and imatinib-resistant (K562-RC, K562-RD) CML cell lines.
  • Assessed cell viability using resazurin assay.
  • Analyzed drug transporter activity, cell death, proliferation, and cell cycle distribution via flow cytometry.

Main Results:

  • Resistant CML models exhibited increased P-gp and BCRP activity compared to sensitive cells.
  • Elacridar monotherapy induced apoptosis but lacked cytostatic effects and did not reach IC50.
  • Combining elacridar (250 nM) with imatinib re-sensitized resistant cells, requiring 5-10 times lower imatinib concentrations.
  • The combination therapy enhanced apoptosis markers (cleaved-caspase-3, cleaved-PARP), induced DNA damage, reduced proliferation, and caused S-phase arrest.

Conclusions:

  • Elacridar, in combination with imatinib, effectively overcomes imatinib resistance in CML models.
  • The combination strategy targets efflux transporters, re-sensitizes resistant CML cells, and induces significant anti-leukemic effects.
  • Elacridar plus imatinib represents a promising therapeutic approach for managing TKI-resistant CML.
Keywords:
ABC transporter inhibitorsapoptosiselacridarimatinib resistance

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