Redox Modulation of Adjacent Thiols in VLA-4 by AS101 Converts Myeloid Leukemia Cells from a Drug-Resistant to Drug-Sensitive State

Abstract

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.

Sensitizing B- and T- cell Lymphoma Cells to Paclitaxel/Abraxane–Induced Death by AS101 via Inhibition of the VLA-4–IL10–Survivin Axis

“…These events initiate by interaction of AS101 with the VLA-4 integrin and terminate with the inhibition of survivin expression by lymphoma cells resulting in increased sensitivity of lymphoma cells to paclitaxel or Abraxane. We have recently shown that AS101 inactivates the VLA-4 integrin by redox modulation of vicinal thiols within the exofacial membranal side (34). This activity accounted for the conversion of resistant to chemotherapy-sensitive acute myelogenous leukemia cells in vivo (34) and to .…”

“…We have recently shown that AS101 inactivates the VLA-4 integrin by redox modulation of vicinal thiols within the exofacial membranal side (34). This activity accounted for the conversion of resistant to chemotherapy-sensitive acute myelogenous leukemia cells in vivo (34) and to . The data represent mean AE SE of three different experiments (A).…”

“…This activity accounted for the conversion of resistant to chemotherapy-sensitive acute myelogenous leukemia cells in vivo (34) and to favorable activities in murine models of autoimmune diseases (35,36). Figure 4A shows that AS101 inhibits the attachment of lymphoma cells to the VLA-4 ligand VCAM-1 in a dose-dependent manner, suggesting inhibition of VLA-4 activity in these cells.…”

The effect of the novel tellurium compound AS101 on autoimmune diseases

“…1), currently being evaluated in Phase II clinical trials in psoriasis patients (unpublished data) and in the prevention of bone marrow toxicity induced by chemotherapy in cancer patients [17]. This compound is a potent immunomodulator both in vitro and in vivo with a variety of potential therapeutic applications [7,11,13,14,16,17,25,26]. Accumulated evidence suggests that much of the biological activity of AS101 and other Te IV compounds such as SAS is directly related to its specific chemical interactions with cysteine thiol residues.…”

“…Anti-inflammatory activity [10][11][12][13] Anti-viral activity [14,15] Chemosensitization of cancer cells [16] Prevention of chemotherapy induced toxicity [17] SAS…”