The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas

Vikas Sehdev, Ahmed Katsha, Jeffrey Ecsedy, Alexander Zaika, Abbes Belkhiri, Wael El-Rifai

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs. METHODS: After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively. RESULTS: By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P <.001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P <.01) that was further enhanced by docetaxel (P <.001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P <.01) was significantly enhanced with the combination treatment (P <.001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P <.001). CONCLUSIONS: The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.

Original languageEnglish (US)
Pages (from-to)904-914
Number of pages11
JournalCancer
Volume119
Issue number4
DOIs
StatePublished - Feb 15 2013
Externally publishedYes

Fingerprint

docetaxel
Aurora Kinase A
Adenocarcinoma
Cell Death
Growth
Neoplasms
Cell Survival
Cell Cycle
Heterografts
Xenograft Model Antitumor Assays
Proteins
Western Blotting
Cell Line
Polyploidy
MLN 8237
Gene Amplification
G1 Phase
Tumor Burden
Caspase 3

Keywords

  • alisertib
  • apoptosis
  • Aurora kinase A
  • cancer
  • docetaxel
  • esophagus
  • mitosis
  • stomach

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas. / Sehdev, Vikas; Katsha, Ahmed; Ecsedy, Jeffrey; Zaika, Alexander; Belkhiri, Abbes; El-Rifai, Wael.

In: Cancer, Vol. 119, No. 4, 15.02.2013, p. 904-914.

Research output: Contribution to journalArticle

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abstract = "Background: Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs. METHODS: After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively. RESULTS: By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P <.001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P <.01) that was further enhanced by docetaxel (P <.001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P <.01) was significantly enhanced with the combination treatment (P <.001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P <.001). CONCLUSIONS: The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.",
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T1 - The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas

AU - Sehdev, Vikas

AU - Katsha, Ahmed

AU - Ecsedy, Jeffrey

AU - Zaika, Alexander

AU - Belkhiri, Abbes

AU - El-Rifai, Wael

PY - 2013/2/15

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N2 - Background: Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs. METHODS: After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively. RESULTS: By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P <.001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P <.01) that was further enhanced by docetaxel (P <.001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P <.01) was significantly enhanced with the combination treatment (P <.001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P <.001). CONCLUSIONS: The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.

AB - Background: Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs. METHODS: After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively. RESULTS: By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P <.001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P <.01) that was further enhanced by docetaxel (P <.001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P <.01) was significantly enhanced with the combination treatment (P <.001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P <.001). CONCLUSIONS: The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.

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KW - esophagus

KW - mitosis

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