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Antitumor Effect of ß2-Microglobulin in Leukemic Cell-bearing Mice via Apoptosis-inducing Activity

Activation of Caspase-3 and Nuclear Factor-B¹

Department of Hematology, Jichi Medical School, Tochigi 329-04 [M. M., Y. T., H. T., M. Uw., M. Ue., R. I., Y. F., K. O., K. H.]; Biochemical Research Laboratory, Morinaga Milk Industry Co. Ltd., Kanagawa 228 [M. T., Y. M., M. I., T. I., M. Y., H. H.]; Department of Biochemistry, Kyoritsu College of Pharmacy, Tokyo 105 [T. K.]; Department of Intractable Disease, International Medical Center of Japan, Tokyo [Y. I.]; and Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170-8455 [K. H.], Japan

We have reported previously that ß2-microglobulin (ß2m) induces apoptosis in leukemic cells in vitro, and that an interaction between ß2m and HLA class I antigen induces apoptosis. Here we examined whether ß2m can induce apoptosis in leukemic cells in vivo and whether it has an antitumor effect in tumor-bearing mice. Daily administration of 50 or 250 µg of ß2m induced apoptosis and an antitumor effect on K562 leukemia cell-bearing mice in the same manner as tumor necrosis factor-. In tumor tissues in ß2m-treated mice, both caspase-3 and nuclear factor-B (NF-B) were stained more strongly than in control mice by anti-caspase-3 and anti-NF-B p65/Rel A polyclonal antibodies. We also observed the in vivo immunological effects of ß2m on lymphoid and hematopoietic organs, such as thymus, bone marrow, Peyer’s patches, liver, and spleen in normal mice. Using antibodies against caspase-3 and NF-B, immunohistochemical staining showed that no specific tissues were damaged or stained in normal mice. We conclude that ß2m stimulates caspase-3 and NF-B pathways to induce apoptosis, making it a useful approach to a new therapy for leukemia.

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