Treatment with the tellurium compound AS101 inhibits acute myeloid leukemia cells (AML) invasion and migration

Abstract

Adhesion molecules, such as integrins, enable acute myeloid leukemia (AML) cells, which travel in the bloodstream, to adhere to the vessels walls. This adhesion is a prerequisite for extra vascular leukemic cell infiltration. The penetrating cells reach vital organs, proliferate and damage the functionality of the tissue which aggravates the patient's condition. The Tellurium compound, AS101, is known for its ability to inhibit specific integrins by Oxidizing key cysteines within the integrins. In this study we found that AS101 can reduce the attachment of human U937 AML cell that expresses high levels of the a4b1 (VLA‐4) integrin to its ligands FN and VCAM‐1. furthermore, AS101 also inhibited the attachment of U937 to the HUVEC human endothelial cells, which express high levels of VCAM‐1 in the presents of TNF‐α. Exposure of U937 cells to AS101 inhibited the pFAK‐ pAKT‐ pGSK signaling, known to be involved in the penetration and migration of cells. AS101 is shown to inhibits the secretion of active MMP‐2 and MMP‐9, enabling cells to penetrate the ECM. Importantly, AS101 could prevent infiltration and migration of AML cells, provided they highly express VLA‐4. This was demonstrated by using patients' AML cells that express high or low levels of the VLA‐4 integrin. In vivo, AS101 prevents invasion of AML cells to the spleen and increase the survival of mice significantly when combined with the chemotherapy ara‐c. This result suggests that the AS101 compound may delay and even prevent the infiltration of the leukemic cells and by doing so, to increase the chances for recovery of the AML patients.