The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT.
The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing. MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Combination therapy induced synergistic tumor-cell death in MM cell lines and primary MM plasma cells. Cell death was rapid and associated with increased caspase 3, 8, and 9 cleavage and concomitant down-regulation of p-AKT. Down-regulation of p-AKT was seen only in combination therapy and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild-type AKT, or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important, supporting bortezomib followed by lonafarnib as the optimal schedule. The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma-cell death and warrants further preclinical and clinical studies.
David
Ebenezer
E
Winship Cancer Institute, Emory University, 1365 Clifton Rd, Building C, Rm 4004, Atlanta, GA 30322, USA.
Sun
Shi-Yong
SY
Waller
Edmund K
EK
Chen
Jing
J
Khuri
Fadlo R
FR
Lonial
Sagar
S
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
D001897:Boronic Acids; D000069286:Bortezomib; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D010880:Piperidines; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes