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 S Perry, Xiaobing Liu, Amit Agarwal, Laurence S. Cooke, Daniel O. Persky, Deyu Chen, Thomas P Miller, Daruka Mahadevan

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 2013

Fingerprint

Peripheral T-Cell Lymphoma
Non-Hodgkin's Lymphoma
Apoptosis
Cell Line
Therapeutics
Clinical Trials
MLN 8237
T-Cell Lymphoma
Inhibitory Concentration 50
Flow Cytometry
Phosphotransferases
Phosphorylation
Cell Proliferation

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

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

In: Leukemia Research, Vol. 37, No. 4, 04.2013, p. 434-439.

Research output: Contribution to journalArticle

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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.",
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AU - Perry, Catherine S

AU - Liu, Xiaobing

AU - Agarwal, Amit

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AU - Persky, Daniel O.

AU - Chen, Deyu

AU - Miller, Thomas P

AU - Mahadevan, Daruka

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