Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Targeting GLUT1 in acute myeloid leukemia to overcome cytarabine resistance.

Abstract

A key alteration in cancer metabolism is an increase in glucose uptake mediated by the glucose transporters (GLUT). Otto Warburg observed already in the 1950s that glycolysis was increased in many tumors, and this is now called the Warburg effect.1 Interestingly, a distinct glucose metabolic signature was recently described for acute myeloid leukemia (AML), showing that enhanced glycolysis correlates with decreased sensitivity for chemotherapy (cytarabine, Ara-C) and poor prognosis.2 AML is the most common acute leukemia in adults and is associated with poor survival, especially in patients >60 years, an age group in which only 5-15% are cured. Moreover, older patients who cannot tolerate intensive chemotherapy have a median overall survival of only 5- 10 months. Thus, novel therapeutic approaches are needed to improve the cure rates of AML. Interestingly, defective GLUT1-mediated glucose uptake was shown to impair AML cell proliferation, and transplantation of GLUT1-deleted murine AML cells attenuated AML development in mice, suggesting that GLUT1 plays an important role in AML.3 Thus, targeting GLUT1 may represent a novel therapeutic vulnerability in AML by overcoming Ara-C resistance. However, there are still no clinically available drugs targeting GLUT, which may partly be due to the lack of suitable in vitro drug-screening systems. Here we present a detailed structural and functional analysis of compounds that inhibit glucose transporters and sensitize AML cells for chemotherapy. GLUT1 is an integral membrane protein