Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms.
BACKGROUND
Interactions between the protein synthesis inhibitor homoharringtonine (HHT) and the proteasome inhibitor bortezomib were investigated in DLBCL and mantle cell lymphoma cells (MCL).


METHODS
Various DLBCL and MCL cells were exposed to HHT and bortezomib alone or together after which apoptosis and signaling pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival.


RESULTS
HHT and bortezomib co-administration synergistically induced apoptosis in GC-, ABC- and double-hit DLBCL cells. Similar interactions were observed in MCL cells and in primary lymphoma cells. HHT/bortezomib co-administration diminished binding of MCL-1 to both BAK and NOXA. Knock-down of NOXA significantly diminished lethality whereas MCL-1 knock-down or ectopic NOXA expression increased cell death. Notably, HHT/bortezomib lethality was dramatically reduced in BAK knockout or knockdown cells. Finally, HHT/bortezomib co-administration significantly improved survival compared to single agents in GC- and ABC- xenograft models while exhibiting little toxicity.


CONCLUSIONS
These findings indicate that HHT and bortezomib cooperate to kill DLBCL and MCL cells through a process involving MCL-1 down-regulation, NOXA up-regulation, and BAK activation. They also suggest that a strategy combining HHT with bortezomib warrants attention in DLBCL and MCL.
['Nguyen|Tri|T|', 'Parker|Rebecca|R|', 'Zhang|Yu|Y|', 'Hawkins|Elisa|E|', 'Kmieciak|Maciej|M|', 'Craun|William|W|', 'Grant|Steven|S|http://orcid.org/0000-0003-4452-9320']
D000818:Animals D017209:Apoptosis D000069286:Bortezomib D045744:Cell Line, Tumor D015536:Down-Regulation D004357:Drug Synergism D000077863:Homoharringtonine D006801:Humans D016403:Lymphoma, Large B-Cell, Diffuse D020522:Lymphoma, Mantle-Cell D051379:Mice D016688:Mice, Inbred NOD D016513:Mice, SCID D064549:Myeloid Cell Leukemia Sequence 1 Protein D061988:Proteasome Inhibitors D019253:Proto-Oncogene Proteins c-bcl-2 D015398:Signal Transduction D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
Bortezomib Mantle cell lymphoma Diffuse large B-cell lymphoma Homoharringtonine (Omacataxine)