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

Content Provider	Semantic Scholar
Author	Francis, Lanie K. Alsayed, Yazan Leleu, Xavier Jia, Xiaoying Singha, Ujjal K. Anderson, Judith Esther Lu, Ganwei Ehrlich, Lori A. Dimmock, Elizabeth A. Lentzsch, Suzanne Hideshima, Teru Roodman, Garson David Ghobrial, Irene M.
Copyright Year	2006
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.
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/12/22/6826.full.pdf
PubMed reference number	17121904v1
Volume Number	12
Issue Number	22
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Language	English
Access Restriction	Open
Subject Keyword	1-Phosphatidylinositol 3-Kinase Apoptosis Bone Marrow Cell Cycle Arrest Critical Pathways Cultured Cell Line FRAP1 protein, human HSP90 Heat-Shock Proteins Heat shock proteins Heat-Shock Response Mammals Multiple Myeloma Nanomole Osteoclasts PARP1 protein, human Patients Proto-Oncogene Proteins c-akt Ribose Sirolimus incubated mTOR Inhibitor tanespimycin
Content Type	Text
Resource Type	Article