Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment

Wenqing Qi, Catherine Spier, Xiaobing Liu, Amit Agarwal, Laurence S. Cooke, Daniel O. Persky, Deyu Chen, Thomas P. Miller, Daruka Mahadevan

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. Alisertib (MLN8237) an investigational agent that inhibits Aurora A Ser/Thr kinase has shown activity in PTCL patients. Here we demonstrate that aurora A and B are highly expressed in T-cell lymphoma cell lines. In PTCL patient samples aurora A was positive in 3 of 24 samples and co-expressed with aurora B. Aurora B was positive in tumor cells in 22 of 32 samples. Of the subtypes of PTCL, aurora B was over-expressed in PTCL (NOS) [73%], T-NHL [100%], ALCL (Alk-Neg) [100%] and AITL [100%]. Treatment with MLN8237 inhibited PTCL cell proliferation in CRL-2396 and TIB-48 cells with an IC50 of 80-100nM. MLN8237 induced endo-reduplication in a dose and time dependent manner in PTCL cell lines leading to apoptosis demonstrated by flow cytometry and PARP-cleavage at concentrations achieved in early phase clinical trials. Moreover, inhibition of HisH3 and aurora A phosphorylation was dose dependent and strongly correlated with endo-reduplication. The data provide a sound rationale for aurora inhibition in PTCL as a therapeutic modality and warrants clinical trial evaluation.

Original languageEnglish (US)
Pages (from-to)434-439
Number of pages6
JournalLeukemia Research
Volume37
Issue number4
DOIs
StatePublished - Apr 1 2013

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Keywords

  • Apoptosis
  • Aurora kinases
  • Cell proliferation
  • Immunohistochemistry
  • MLN8237 (Alisertib)
  • Peripheral T-cell lymphoma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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