AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas

Wenqing Qi, Xiaobing Liu, Laurence S. Cooke, Daniel O. Persky, Thomas P Miller, Matthew Squires, Daruka Mahadevan

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC 50 < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation.

Original languageEnglish (US)
Pages (from-to)2997-3005
Number of pages9
JournalInternational Journal of Cancer
Volume130
Issue number12
DOIs
StatePublished - Jun 15 2012

Fingerprint

Aurora Kinases
docetaxel
B-Cell Lymphoma
Growth
Neoplasms
Apoptosis
Non-Hodgkin's Lymphoma
1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
Endoreduplication
Vinca Alkaloids
Mantle-Cell Lymphoma
Cell Line
Taxoids
Growth Inhibitors
Protein-Serine-Threonine Kinases
Eukaryotic Cells
Heterografts
Microtubules

Keywords

  • AT9283
  • aurora kinase inhibitor
  • docetaxel
  • mantle cell lymphoma
  • non-Hodgkin lymphoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. / Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S.; Persky, Daniel O.; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka.

In: International Journal of Cancer, Vol. 130, No. 12, 15.06.2012, p. 2997-3005.

Research output: Contribution to journalArticle

Qi, Wenqing ; Liu, Xiaobing ; Cooke, Laurence S. ; Persky, Daniel O. ; Miller, Thomas P ; Squires, Matthew ; Mahadevan, Daruka. / AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. In: International Journal of Cancer. 2012 ; Vol. 130, No. 12. pp. 2997-3005.
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