Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition

Naoya Mimura, Teru Hideshima, Toshiyasu Shimomura, Rikio Suzuki, Hiroto Ohguchi, Ola Rizq, Shohei Kikuchi, Yasuhiro Yoshida, Francesca Cottini, Jana Jakubikova, Diana Cirstea, Gullu Gorgun, Jiro Minami, Yu Tzu Tai, Paul G. Richardson, Teruhiro Utsugi, Atsushi Iwama, Kenneth C. Anderson

Research output: Contribution to journalArticle

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Abstract

The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM.

Original languageEnglish (US)
Pages (from-to)4458-4469
Number of pages12
JournalCancer Research
Volume74
Issue number16
DOIs
StatePublished - Aug 15 2014
Externally publishedYes

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Endoplasmic Reticulum Stress
Proteasome Endopeptidase Complex
Multiple Myeloma
Transcription Factor CHOP
3-amino-1-methyl-3-(4-(3-phenyl-5H- imidazo(1,2-c)pyrido(3,4-e)(1,3)oxazin-2-yl)phenyl)cyclobutanol
Proteasome Inhibitors
Autophagy
Growth
Mesenchymal Stromal Cells
Phosphatidylinositol 3-Kinases
Heterografts
Oral Administration
Interleukin-6
Blood Cells
Down-Regulation
Bone Marrow
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. / Mimura, Naoya; Hideshima, Teru; Shimomura, Toshiyasu; Suzuki, Rikio; Ohguchi, Hiroto; Rizq, Ola; Kikuchi, Shohei; Yoshida, Yasuhiro; Cottini, Francesca; Jakubikova, Jana; Cirstea, Diana; Gorgun, Gullu; Minami, Jiro; Tai, Yu Tzu; Richardson, Paul G.; Utsugi, Teruhiro; Iwama, Atsushi; Anderson, Kenneth C.

In: Cancer Research, Vol. 74, No. 16, 15.08.2014, p. 4458-4469.

Research output: Contribution to journalArticle

Mimura, N, Hideshima, T, Shimomura, T, Suzuki, R, Ohguchi, H, Rizq, O, Kikuchi, S, Yoshida, Y, Cottini, F, Jakubikova, J, Cirstea, D, Gorgun, G, Minami, J, Tai, YT, Richardson, PG, Utsugi, T, Iwama, A & Anderson, KC 2014, 'Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition', Cancer Research, vol. 74, no. 16, pp. 4458-4469. https://doi.org/10.1158/0008-5472.CAN-13-3652
Mimura, Naoya ; Hideshima, Teru ; Shimomura, Toshiyasu ; Suzuki, Rikio ; Ohguchi, Hiroto ; Rizq, Ola ; Kikuchi, Shohei ; Yoshida, Yasuhiro ; Cottini, Francesca ; Jakubikova, Jana ; Cirstea, Diana ; Gorgun, Gullu ; Minami, Jiro ; Tai, Yu Tzu ; Richardson, Paul G. ; Utsugi, Teruhiro ; Iwama, Atsushi ; Anderson, Kenneth C. / Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. In: Cancer Research. 2014 ; Vol. 74, No. 16. pp. 4458-4469.
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abstract = "The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM.",
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T1 - Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition

AU - Mimura, Naoya

AU - Hideshima, Teru

AU - Shimomura, Toshiyasu

AU - Suzuki, Rikio

AU - Ohguchi, Hiroto

AU - Rizq, Ola

AU - Kikuchi, Shohei

AU - Yoshida, Yasuhiro

AU - Cottini, Francesca

AU - Jakubikova, Jana

AU - Cirstea, Diana

AU - Gorgun, Gullu

AU - Minami, Jiro

AU - Tai, Yu Tzu

AU - Richardson, Paul G.

AU - Utsugi, Teruhiro

AU - Iwama, Atsushi

AU - Anderson, Kenneth C.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM.

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