A considerable volume of evidence indicates that cancer stem cells are responsible for the development of different types of tumorsand therefore share the same phenotypes. The VLA- integrin is expressed on hematopoietic stem cells and plays an important role in their homing to bone marrow. Furthermore, Studies have shown that in acute myeloid leukemia (AML) the interaction between vla-4 on leukemic blast cells with its ligand fibronectin on bone marrow stromal cells results in induced survival and resistant to chemotherapy. We show that the non toxic compound AS101, previously shown to exert anti tumoral effects both in vitro and in vivo, sensitizes AML cells to ARA-C by inactivating the VLA-4 integrin expressed on leukemic blasts. This activity is associated with a significant decrease in pAkt and Bcl-2.
In a model of SCID mice implanted with leukemic cells co-treatment with AS101 and chemotherapy significantly increased mice survival while chemotherapy alone exerted only a modest effect. Moreover, mice transplanted with AML cells that express low VLA-4, considerably reacted to chemotherapy alone as expressed by increased survival, while co-treatment with AS101 resulted in similar effects. More importantly, AS101 increases migration of leukemic blast cells expressing high VLA-4 from the Bone-Marrow to the peripheral blood enabling their sensitization to chemotherapy.
We propose that treatment with AS101 currently used in treatment of cancer patients, combined with chemotherapy,has a potential to eradicate MRD and prolong survival of AML patients by inactivating VLA-4.
Moreover, by this same mechanism, AS101 may be able to destroy other cancer stem cells which attach to their microenvironmental niche by this integrin being the source for tumorgenesis.
