title: In vitro synergism between LFA-1 targeting leukotoxin (Leukothera™) and standard chemotherapeutic agents in leukemia cells.
abstract: Leukotoxin (Leukothera™; LtxA) is a bacterial protein and experimental therapeutic that binds leukocyte function antigen (LFA-1) on white blood cells (WBCs) and induces cell death via apoptosis or necrosis. We previously found that LtxA preferentially targets WBCs with high levels of activated LFA-1, which is characteristic of many leukemias and lymphomas, and showed that LtxA exhibits significant anti-leukemia activity in vivo using the humanized SCID mouse model. In this report, we demonstrate that LtxA induces very rapid (1h) apoptosis in acute monocytic leukemia THP-1 cells characterized by binding of annexin V to cells, loss of mitochondrial membrane potential, depletion of cellular ATP, and fragmentation of chromosomal DNA. We tested the activity of LtxA in combination with the standard chemotherapeutic agents, etoposide, mitoxantrone, daunorubicin, busulfan, and imatinib against several leukemia cell lines, including THP-1, GDM-1, HL-60, and KU-812 cells. LtxA exhibited synergism with all the drugs, and the levels of synergy were dependent on the doses used and cell lines examined. In general, the greatest level of synergy was observed with LtxA and etoposide or imatinib. Combination index (CI) values were less than 0.1 for many of the combinations, indicating very strong synergism. In addition, LtxA alone was cytotoxic to primary cells from newly diagnosed, relapsed, and refractory patients with different hematological malignancies. Thus, LtxA is highly effective at inducing rapid apoptosis both as a single agent and in combination with approved leukemia therapies.
authors.affiliation: Department of Oral Biology, New Jersey Dental School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Anukriti
authors.initials: A
authors.lastname: Gupta
authors.forename: Amy
authors.initials: A
authors.lastname: Le
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Belinka
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kachlany
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002066:Busulfan / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000008:administration & dosage; D004347:Drug Interactions; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D005098:Exotoxins / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008942:Mitoxantrone / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D005098:Exotoxins; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D010879:Piperazines; D011743:Pyrimidines; C018579:leukotoxin; D005047:Etoposide; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D008942:Mitoxantrone; D002066:Busulfan; D003630:Daunorubicin