Interaction between the integrin VLA-4 on acute myelogenous leukemia (AML) cells with stromal fibronectin is a decisive factor in chemotherapeutic resistance. In this study, we provide a rationale for a drug repositioning strategy to blunt integrin activation in AML cells and restore their sensitivity to chemotherapy. Specifically, we demonstrate that the nontoxic tellurium compound AS101, currently being evaluated in clinical trials, can abrogate the acquired resistance of AML. Mechanistic investigations revealed that AS101 caused redox inactivation of adjacent thiols in the exofacial domain of VLA-4 after its ligation to stromal fibronectin. This effect triggered cytoskeletal conformational changes that decreased PI3K/Akt/Bcl2 signaling, an obligatory step in chemosensitization by AS101. In a mouse xenograft of AML derived from patient leukemic cells with high VLA-4 expression and activity, we demonstrated that AS101 abrogated drug resistance and prolonged survival in mice receiving chemotherapy. Decreased integrin activity was confirmed on AML cells in vivo. The chemosensitizing activity of AS101 persisted in hosts with defective adaptive and innate immunity, consistent with evidence that integrin deactivation was not mediated by heightening immune attack. Our findings provide a mechanistic rationale to reposition the experimental clinical agent, AS101, to degrade VLA-4-mediated chemoresistance and improve clinical responses in patients with AML. Cancer Res; 74(11); 3092-103. Ó2014 AACR.

<p>PDF file - 1318K, Fig S4. DTNB or AS101 sensitize high VLA-4 expressing lekemic cells from AML patients, to chemotherapy.</p>

<p>PDF file - 981K, Fig. S6: Inhibition of pAkt mediates AS101's activity involving chemotherapy-induced AML cell death as tested by subG1 accumulation.</p>

<p>PDF file - 1027K, Fig. S1: AS101 induces chemotherapy-induced apoptotic death by decreasing VLA-4 activity.</p>

<p>PDF file - 981K, Fig. S6: Inhibition of pAkt mediates AS101's activity involving chemotherapy-induced AML cell death as tested by subG1 accumulation.</p>

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<p>PDF file - 1086K, Fig. S5: Knocking out VLA-4 in mouse myelomonocytic leukemia cells or human AML leukemic cells induces drug sensitivity which is not further enhanced by AS101.</p>

<p>PDF file - 1142K, Fig S7. Treatment with AS101 prevents MRD in a xenograft mouse model of AML.</p>