Journal
BIOCHEMICAL PHARMACOLOGY
Volume 81, Issue 9, Pages 1106-1115Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2011.02.010
Keywords
Aurora B; AZD1152; Burkitt's lymphoma; Hodgkin's lymphoma; Apoptosis
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Funding
- Grants-in-Aid for Scientific Research [21590331] Funding Source: KAKEN
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We studied the effects of AZD1152, an Aurora B kinase inhibitor, on Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HL) in human tissues and cell cultures and in a murine xenograft model of lymphoma. Aurora kinase A and B levels were assessed by RT-PCR and immunohistochemistry. They were aberrantly expressed in BL and HL cell lines, and in lymph nodes from patients with BL and HL. Next, activation of the Aurora B promoter was detected by reporter gene assays. The promoter activity of Aurora B kinase was high in BL cell lines and the Aurora B promoter contained a positive regulatory region between -74 and -104 from the transcription initiation site. AZD1152-hQPA had antiproliferative effects in the BL and HL cell lines studied; inhibited the phosphorylation of histone H3 and retinoblastoma proteins, and resulted in cells with >4 N DNA content. AZD1152-hQPA induced caspase-dependent apoptosis of some cell lines, demonstrated by loss of mitochondria] membrane potential, activation of caspase-9, followed by activation of caspase-3. This effect was accompanied by the inhibition of survivin expression. In vivo efficacy was determined in NOD/SCID/gamma c(null) mice implanted with the Ramos human BL cell line. AZD1152 had anti-tumour effects in this murine xenograft model. There preclinical data suggest that the inhibition of Aurora B kinase is a potentially useful therapeutic strategy in BL and HL. (C) 2011 Elsevier Inc. All rights reserved.
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