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


METHODS
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.
Francis
Lanie K
LK
University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Department of Internal Medicine, Pittsburgh, Pennsylvania, USA.
Alsayed
Yazan
Y
Leleu
Xavier
X
Jia
Xiaoying
X
Singha
Ujjal K
UK
Anderson
Judith
J
Timm
Michael
M
Ngo
Hai
H
Lu
Ganwei
G
Huston
Alissa
A
Ehrlich
Lori A
LA
Dimmock
Elizabeth
E
Lentzsch
Suzanne
S
Hideshima
Teru
T
Roodman
G David
GD
Anderson
Kenneth C
KC
Ghobrial
Irene M
IM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus