Abstract:
The interaction between very late antigen (VLA)-4 on acute myelogenous leukemis (AML) cells and stromal fibronectin is a decisive factor in drug resistance of leukemic cells. This recognition indicates the need of finding effective means of controlling VLA-4 activation. This study demonstrates an alternative and unique approach that may supersede existing strategies of cellular integrin inactivation. We show that the non toxic small molecule tellurium compound Ammonium trichloro(dioxyethylene-O-O')tellurate(AS101), currently used in clinical studies, abrogates the acquired resistance of AML established cultures and of leukemic cells from AML patients, to drug-induced apoptosis by redox inactivation of the exofacial domain of very late antigen (VLA)-4 upon Fibronectin ligation or upon stromal cells interaction.. This integrin deactivation was followed by decreased PI3K/Akt/Bcl2 signaling, an obligatory event mediating AS101’s sensitizing effect. Importantly, this unique concept of cellular VLA-4 inactivation had physiological meanings. In a xenograft model in which mice were inoculated with leukemic cells from AML patients with high VLA-4 expression and activity, treatment with AS101 abrogated drug resistance and prolonged survival of treated mice when combined with chemotherapy. Thus, redox modulation of cellular VLA-4 by non toxic agents such as AS101, combined with chemotherapy, holds promise to convert resistant to chemotherapy-sensitive in bone marrow of AML patients.
