Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms
Authors: William Craun
Elisa Hawkins
Yu Zhang
Maciej Kmieciak
Tri Nguyen
Rebecca Parker
Steven Grant
Journal: BMC Cancer (2018)
Discipline: CLINICAL MEDICINE
Keywords: Bortezomib; Diffuse large B-cell lymphoma; Homoharringtonine (Omacataxine); Mantle cell lymphoma.
Affiliations: Division of Hematology/Oncology, Virginia Commonwealth University Richmond, Room 229 Goodwin Research Building, 401 College Street, Richmond, VA, 23229, USA., Massey Cancer Center, Virginia Commonwealth University Richmond, Richmond, VA, USA., Division of Hematology/Oncology, Virginia Commonwealth University Richmond, Room 229 Goodwin Research Building, 401 College Street, Richmond, VA, 23229, USA. ., Palliative Care, Virginia Commonwealth University Richmond, Richmond, VA, USA. ., Department of Biochemistry, Virginia Commonwealth University Richmond, Richmond, VA, USA. ., Human and Molecular Genetics, Virginia Commonwealth University Richmond, Richmond, VA, USA. ., Massey Cancer Center, Virginia Commonwealth University Richmond, Richmond, VA, USA. .

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. 

Retracted: No

PubPeer comments:
 After the Dasmahapatra scandal with nine retractions and a long list of problematic issues in publications from this group, I feel I have the right to be skeptical. In Figure 6, I get an impression that the authors present data which is a variation around the same group of mice. In both Figure 6A and B many of the mice show surprisingly similarities despite different treatment. Dasmahapatra used to copy and past images of mice. In this case they are not identical, but the similarities are too many between mice that have undergone different treatment. ![file] ![file] ![file] ![file] ![file] ,