Abstract

OBJECTIVE: Based on our previous findings that Pim-1 was expressed on the cell surface and could be targeted with a highly specific anti-Pim-1 monoclonal antibody (P9), this study aims to evaluate the possibility that Pim-1 could be targeted for the treatment of human leukemia. MATERIALS AND METHODS: Pim-1 expression was investigated in a series of human leukemia cell lines with immunohistochemistry and flow cytometry. The inhibitory effect of P9 on cell proliferation was evaluated with (3)H-thymidine incorporation assay. Cell apoptosis was assayed with Annexin-V/propidium iodide dual staining. The in vivo effect of P9 was evaluated with xenograft tumor models in severe combined immunodeficient mice. RESULTS: Pim-1 expression varied depending on the cell lines and correlated with the inhibitory effects mediated by P9. An association between Pim-1 expression and drug resistance was observed. Although the drug-resistant CEM/A7R cells were highly resistant to cytotoxic P-glycoprotein substrates, their growth was inhibited by P9 as demonstrated by in vitro proliferation assay and in vivo inhibition of xenograft tumors. P9 had little effect on P-glycoprotein expression and intracellular Rhodamine 123 accumulation, but it inhibited the phosphorylation of Bad and induced apoptosis. CONCLUSIONS: Pim-1 is variably expressed in leukemia cell lines and associated with drug resistance. Targeting Pim-1 with monoclonal antibody could be explored for the treatment of leukemia and may represent a novel strategy to overcome drug resistance.