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Drug repurposing for targeting cyclic nucleotide transporters in acute leukemias - A missed opportunity

Dominique R Perez1, Larry A Sklar2, Alexandre Chigaev2

  • 1Department of Pathology, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA; Center for Molecular Discovery, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.

Seminars in Cancer Biology
|February 12, 2020
PubMed

Insights

Targeting cyclic AMP (cAMP) efflux via ATP-binding cassette transporters offers a novel therapeutic strategy for acute leukemia. Inhibiting cAMP efflux promotes leukemia cell differentiation and apoptosis, presenting new drug repurposing opportunities.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • The cyclic AMP (cAMP) pathway plays a crucial role in cell differentiation, survival, and apoptosis, making it a significant target in hematological malignancies.
  • Acute leukemia patients often exhibit gene expression profiles linked to heightened pro-survival cAMP activity or reduced pro-apoptotic factors.
  • Existing therapeutic strategies to elevate intracellular cAMP in leukemia cells include using cAMP analogs, stimulating production, or inhibiting degradation.

Purpose of the Study:

  • To explore the potential of targeting cyclic nucleotide efflux mediated by ATP-binding cassette (ABC) transporters as a novel approach to modulate intracellular cAMP levels in acute leukemia.
  • To investigate the therapeutic promise of inhibiting cAMP efflux for treating hematological malignancies.

Main Methods:

  • Focuses on the unexplored approach of targeting cyclic nucleotide efflux via ABC transporters.
  • References preliminary studies demonstrating the effects of inhibiting cAMP efflux on leukemia cells.

Main Results:

  • Inhibition of cAMP efflux has been shown to induce leukemia cell differentiation, growth arrest, and apoptosis in preliminary studies.
  • Targeting cyclic nucleotide transporter activity may reduce extracellular pro-survival signaling in malignant cells, offering broader anticancer benefits.

Conclusions:

  • Modulating intracellular cAMP levels by targeting efflux through ABC transporters represents a promising, yet unexplored, therapeutic avenue for acute leukemia.
  • Inhibiting cyclic nucleotide transporters may offer multifaceted anticancer effects and presents opportunities for drug repurposing in leukemia treatment.
Keywords:
3',5'-cyclic adenosine monophosphate (cAMP)ATP-binding cassette (ABC) transportersAcute lymphoblastic leukemia (ALL)Acute myelogenous leukemia (AML)EffluxInhibitors of cAMP efflux (ICE)

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