Inhibition of the mevalonate pathway potentiates the effects of lenalidomide in myeloma.
The effects of the combination of simvastatin and lenalidomide were analyzed in myeloma. Myeloma cell lines and patient myeloma cells were incubated with different concentrations of lenalidomide, simvastatin, or the combination. Co exposure to simvastatin and lenalidomide resulted in a synergistic reduction of cell viability in myeloma cells. This effect was due to induction of apoptosis and inhibition of proliferation. The combination augmented induction of caspase-8 cleavage and enhanced down-regulation of pStat3. Mevalonate and GGOH abrogated the synergy between lenalidomide and simvastatin. These data provide a rationale for the clinical evaluation of lenalidomide and simvastatin in patients with myeloma.
van der Spek
Ellen
E
Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands. e.vanderspek@umcutrecht.nl
Bloem
Andries C
AC
Lokhorst
Henk M
HM
van Kessel
Berris
B
Bogers-Boer
Lijnie
L
van de Donk
Niels W C J
NW
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D000077269:Lenalidomide; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D017368:Protein Prenylation; D050796:STAT3 Transcription Factor / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D013792:Thalidomide; D019821:Simvastatin; D000077269:Lenalidomide; D008798:Mevalonic Acid