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Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms
- Source :
- BMC Cancer, Vol 18, Iss 1, Pp 1-11 (2018), BMC Cancer
- Publication Year :
- 2018
- Publisher :
- BMC, 2018.
-
Abstract
- 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. Electronic supplementary material The online version of this article (10.1186/s12885-018-5018-x) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Cancer Research
Apoptosis
Lymphoma, Mantle-Cell
Mice, SCID
Bortezomib
Mice
0302 clinical medicine
Mice, Inbred NOD
immune system diseases
hemic and lymphatic diseases
medicine.diagnostic_test
Chemistry
Drug Synergism
Diffuse large B-cell lymphoma
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Up-Regulation
Oncology
Proto-Oncogene Proteins c-bcl-2
030220 oncology & carcinogenesis
Homoharringtonine
Lymphoma, Large B-Cell, Diffuse
Proteasome Inhibitors
medicine.drug
Research Article
Signal Transduction
Programmed cell death
Homoharringtonine (Omacataxine)
Down-Regulation
lcsh:RC254-282
Flow cytometry
03 medical and health sciences
Cell Line, Tumor
Genetics
medicine
otorhinolaryngologic diseases
Animals
Humans
neoplasms
Mantle cell lymphoma
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Proteasome inhibitor
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
Subjects
Details
- Language :
- English
- ISSN :
- 14712407
- Volume :
- 18
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- BMC Cancer
- Accession number :
- edsair.doi.dedup.....bcd7e984b55e4cecdcb8201571048e08