Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma

Lanie K. Francis, Yazan Alsayed, Xavier Leleu, Xiaoying Jia, Ujjal K. Singha, Judith Anderson, Michael Timm, Hai Ngo, Ganwei Lu, Alissa Huston, Lori A. Ehrlich, Elizabeth Dimmock, Suzanne Lentzsch, Teru Hideshima, G. David Roodman, Kenneth C. Anderson, Irene M. Ghobrial

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.

Original languageEnglish (US)
Pages (from-to)6826-6835
Number of pages10
JournalClinical Cancer Research
Volume12
Issue number22
DOIs
StatePublished - Nov 15 2006
Externally publishedYes

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tanespimycin
Sirolimus
Multiple Myeloma
Phosphatidylinositol 3-Kinase
Retinoblastoma
TOR Serine-Threonine Kinases
Cyclin D
Critical Pathways
Poly(ADP-ribose) Polymerases
Caspase 9
Caspase 8
Cyclin D1
Osteoclasts
Heat-Shock Proteins
Cell Cycle Checkpoints
Bone Marrow Cells
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. / Francis, Lanie K.; Alsayed, Yazan; Leleu, Xavier; Jia, Xiaoying; Singha, Ujjal K.; Anderson, Judith; Timm, Michael; Ngo, Hai; Lu, Ganwei; Huston, Alissa; Ehrlich, Lori A.; Dimmock, Elizabeth; Lentzsch, Suzanne; Hideshima, Teru; Roodman, G. David; Anderson, Kenneth C.; Ghobrial, Irene M.

In: Clinical Cancer Research, Vol. 12, No. 22, 15.11.2006, p. 6826-6835.

Research output: Contribution to journalArticle

Francis, LK, Alsayed, Y, Leleu, X, Jia, X, Singha, UK, Anderson, J, Timm, M, Ngo, H, Lu, G, Huston, A, Ehrlich, LA, Dimmock, E, Lentzsch, S, Hideshima, T, Roodman, GD, Anderson, KC & Ghobrial, IM 2006, 'Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma', Clinical Cancer Research, vol. 12, no. 22, pp. 6826-6835. https://doi.org/10.1158/1078-0432.CCR-06-1331
Francis, Lanie K. ; Alsayed, Yazan ; Leleu, Xavier ; Jia, Xiaoying ; Singha, Ujjal K. ; Anderson, Judith ; Timm, Michael ; Ngo, Hai ; Lu, Ganwei ; Huston, Alissa ; Ehrlich, Lori A. ; Dimmock, Elizabeth ; Lentzsch, Suzanne ; Hideshima, Teru ; Roodman, G. David ; Anderson, Kenneth C. ; Ghobrial, Irene M. / Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 22. pp. 6826-6835.
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abstract = "Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.",
author = "Francis, {Lanie K.} and Yazan Alsayed and Xavier Leleu and Xiaoying Jia and Singha, {Ujjal K.} and Judith Anderson and Michael Timm and Hai Ngo and Ganwei Lu and Alissa Huston and Ehrlich, {Lori A.} and Elizabeth Dimmock and Suzanne Lentzsch and Teru Hideshima and Roodman, {G. David} and Anderson, {Kenneth C.} and Ghobrial, {Irene M.}",
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T1 - Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma

AU - Francis, Lanie K.

AU - Alsayed, Yazan

AU - Leleu, Xavier

AU - Jia, Xiaoying

AU - Singha, Ujjal K.

AU - Anderson, Judith

AU - Timm, Michael

AU - Ngo, Hai

AU - Lu, Ganwei

AU - Huston, Alissa

AU - Ehrlich, Lori A.

AU - Dimmock, Elizabeth

AU - Lentzsch, Suzanne

AU - Hideshima, Teru

AU - Roodman, G. David

AU - Anderson, Kenneth C.

AU - Ghobrial, Irene M.

PY - 2006/11/15

Y1 - 2006/11/15

N2 - Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.

AB - Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.

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