Treatment with AS101 sensitizes acute myeloid leukemia cells (AML) to chemotherapy by disrupting the interaction between the integrin VLA-4 and Fibronectin: Mechanisms of action and clinical applications

International Conference & Exhibition on Cancer Science & Therapy

15-17 August 2011 Las Vegas, USA

Benjamin Sredni, Adi Bazar and Yona Kalechman

Scientific Tracks Abstracts: J Cancer Sci Ther

Abstract :

Bone marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML) due to acquired drug resistance - this is induced by the attachment of the integrin receptor VLA-4 on leukemic cells to its ligand fibronectin (FN) on bone marrow stromal cells. We show that the non toxic compound AS101, previously shown to exert anti tumoral effects in-vitro and in-vivo , sensitizes AML cells to ARA-C only when leukemic cells are plated on FN but not on BSA-coated plates. This was associated with a significant decrease in pAkt and Bcl-2. The sensitizing effect of AS101 was also correlated with the ability of AS101 to deactivate VLA on AML cells. In a model of SCID mice implanted with leukemic cells either from established AML cell lines or with leukemic cells expressing high VLA-4, obtained from AML patients, co-treatment with AS101 and chemotherapy significantly increased mice survival while chemotherapy alone exerted only a modest effect. Furthermore, the combined treatment resulted in the elimination of leukemic cells from all organs tested. 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. Importantly, AS101 increases migration of leukemic 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.

Biography :

Prof. Benjamin Sredni, Head of The Cancer, AIDS and Immunology Research Institute at Bar-Ilan University in Israel - completed his Ph.D at Bar-Ilan and was a visiting scientist and associate many times at the Laboratories of Immunology, NIH, , US. Sredni served as Chief Scientist of the Ministry of Health in Israel and is Dean of the School of Graduate Studies at Bar-Ilan. He is a member of numerous reputed scientific organizations and was President of the Israel Association of Immunology. He has published over 175 papers in reputed journals and is guest editor in a special issue of Seminars of Cancer Biology.