Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes.
In this report, we investigated the mechanism responsible for synergistic induction of myeloma cell apoptosis induced by the combination of tipifarnib and bortezomib. Immunofluorescence studies revealed that bortezomib alone resulted in an accumulation of puncta of ubiquitinated proteins that was further enhanced by the addition of tipifarnib. These data suggest inhibition of the degradation of bortezomib-induced aggresomes; and consistent with this possibility, we also observed an increase in p62SQSTM1 in cells treated with the combination. However, autophagy in these cells appears to be normal as LC3BII is present, and autophagic flux appears to be unaffected as demonstrated by the addition of bafilomycin A₁. Together, these data demonstrate that tipifarnib synergizes with bortezomib by inducing protein accumulation as a result of the uncoupling of the aggresome and autophagy pathways.
David
Ebenezer
E
Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, School of Medicine, Atlanta, GA, USA.
Kaufman
Jonathan L
JL
Flowers
Christopher R
CR
Schafer-Hales
Katherine
K
Torre
Claire
C
Chen
Jing
J
Marcus
Adam I
AI
Sun
Shi-Yong
SY
Boise
Lawrence H
LH
Lonial
Sagar
S
D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D015363:Quinolones; D054875:Ubiquitination / Q000187:drug effects
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D015363:Quinolones; D000069286:Bortezomib; C402769:tipifarnib