Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state.
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.
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Adi
A
Layani-Bazar
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Itai
I
Skornick
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Alain
A
Berrebi
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Maor H
MH
Pauker
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Elad
E
Noy
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, MarylandAuthors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Alon
A
Silberman
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Michael
M
Albeck
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Dan L
DL
Longo
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland.
Yona
Y
Kalechman
Authors' Affiliations: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences; Chemistry Department, Bar-Ilan University, Ramat-Gan; Department of Hematology, Kaplan Medical Center, Rehovot, Israel; and Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute on Aging, Baltimore, Maryland srednib@mail.biu.ac.il.
Benjamin
B
Sredni
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005030:Ethylenes / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010084:Oxidation-Reduction / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D020298:U937 Cells; D051025:bcl-Associated Death Protein / Q000378:metabolism
D005030:Ethylenes; D005353:Fibronectins; D039041:Integrin alpha4beta1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D013438:Sulfhydryl Compounds; D051025:bcl-Associated Death Protein; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate