Direct inhibition of human acute myeloid leukemia cell growth by IL-12.
Acute myeloid leukemia is a haematopoietic malignancy originating from the transformation of myeloid progenitors that proliferate and accumulate in the bone marrow. In AML patients the survival rate at 5 years is 40-50% highlighting the need for novel therapies. In this study we have asked whether IL-12, an immuno-modulatory cytokine with anti-tumor activity, may inhibit directly AML cell growth. We show that the human AML cell lines U937, K562 and THP-1 expressed both chains of the IL-12 receptor (R), i.e. IL-12Rβ1 and IL-12Rβ2. IL-12 inhibited the angiogenic potential of AML cells in vitro, but did not affect their survival or proliferation. In vivo experiments were performed using SCID-NOD mice injected intraperitoneally (i.p.) with the human U937 AML cell line and subsequently treated with human recombinant IL-12 or PBS i.p. Histological, immunohistochemical and flow cytometric analyses on explanted tumors revealed that IL-12 reduced new vessel formation, induced apoptosis and inhibited tumor cell proliferation. Studies on a panel of angiogenesis related genes in explanted tumors using PCR arrays showed significantly down-regulated expression of numerous pro-angiogenic genes including VEGF-C, IL-6, IL-8, CXCL1, CXCL6 and alanyl aminopeptidase in IL-12 vs PBS treated mice. This study shows for the first time that IL-12 targets directly AML cell growth and paves the way to further investigation of IL-12 as potential drug for AML treatment.
Ferretti
Elisa
E
Laboratory of Oncology, G. Gaslini Institute, Largo Gaslini 5, 16148 Genova, Italy. elisaferretti@ospedale-gaslini.ge.it
Di Carlo
Emma
E
Cocco
Claudia
C
Ribatti
Domenico
D
Sorrentino
Carlo
C
Ognio
Emanuela
E
Montagna
Daniela
D
Pistoia
Vito
V
Airoldi
Irma
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000494:pharmacology; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020298:U937 Cells
D006131:Growth Inhibitors; D053707:Receptors, Interleukin-12; D018664:Interleukin-12