Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma

Wenqing Qi, Laurence S. Cooke, Xiaobing Liu, Lisa M Rimsza, Denise Roe, Ann Manziolli Daniel O Persky, Thomas P Miller, Daruka Mahadevan

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC50 of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237 + docetaxel enhanced apoptosis by ∼3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.

Original languageEnglish (US)
Pages (from-to)881-890
Number of pages10
JournalBiochemical Pharmacology
Volume81
Issue number7
DOIs
StatePublished - Apr 1 2011

Fingerprint

docetaxel
Mantle-Cell Lymphoma
Tumors
Apoptosis
Neoplasms
Cells
Phosphorylation
Polyploidy
Protein-Serine-Threonine Kinases
Cell proliferation
Eukaryotic Cells
Microarrays
Cell culture
Heterografts
Refractory materials
Histones
Inhibitory Concentration 50
MLN 8237
Lymphoma
Cell Cycle

Keywords

  • Aurora A and B
  • Aurora Inhibitor
  • Docetaxel
  • Mantle cell lymphoma (MCL)
  • MLN8237
  • Non-Hodgkin lymphoma (NHL)

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. / Qi, Wenqing; Cooke, Laurence S.; Liu, Xiaobing; Rimsza, Lisa M; Roe, Denise; Persky, Ann Manziolli Daniel O; Miller, Thomas P; Mahadevan, Daruka.

In: Biochemical Pharmacology, Vol. 81, No. 7, 01.04.2011, p. 881-890.

Research output: Contribution to journalArticle

Qi, Wenqing ; Cooke, Laurence S. ; Liu, Xiaobing ; Rimsza, Lisa M ; Roe, Denise ; Persky, Ann Manziolli Daniel O ; Miller, Thomas P ; Mahadevan, Daruka. / Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. In: Biochemical Pharmacology. 2011 ; Vol. 81, No. 7. pp. 881-890.
@article{c9dd7994dc8c4c54ba62e48969045896,
title = "Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma",
abstract = "Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75{\%} of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC50 of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237 + docetaxel enhanced apoptosis by ∼3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.",
keywords = "Aurora A and B, Aurora Inhibitor, Docetaxel, Mantle cell lymphoma (MCL), MLN8237, Non-Hodgkin lymphoma (NHL)",
author = "Wenqing Qi and Cooke, {Laurence S.} and Xiaobing Liu and Rimsza, {Lisa M} and Denise Roe and Persky, {Ann Manziolli Daniel O} and Miller, {Thomas P} and Daruka Mahadevan",
year = "2011",
month = "4",
day = "1",
doi = "10.1016/j.bcp.2011.01.017",
language = "English (US)",
volume = "81",
pages = "881--890",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma

AU - Qi, Wenqing

AU - Cooke, Laurence S.

AU - Liu, Xiaobing

AU - Rimsza, Lisa M

AU - Roe, Denise

AU - Persky, Ann Manziolli Daniel O

AU - Miller, Thomas P

AU - Mahadevan, Daruka

PY - 2011/4/1

Y1 - 2011/4/1

N2 - Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC50 of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237 + docetaxel enhanced apoptosis by ∼3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.

AB - Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC50 of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237 + docetaxel enhanced apoptosis by ∼3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.

KW - Aurora A and B

KW - Aurora Inhibitor

KW - Docetaxel

KW - Mantle cell lymphoma (MCL)

KW - MLN8237

KW - Non-Hodgkin lymphoma (NHL)

UR - http://www.scopus.com/inward/record.url?scp=79952565110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952565110&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2011.01.017

DO - 10.1016/j.bcp.2011.01.017

M3 - Article

C2 - 21291867

AN - SCOPUS:79952565110

VL - 81

SP - 881

EP - 890

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 7

ER -