Degrasyn potentiates the antitumor effects of bortezomib in mantle cell lymphoma cells in vitro and in vivo: therapeutic implications.
Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that has increased in incidence over the past few decades and is incurable, usually poorly responsive to standard chemotherapy combinations, and associated with poor prognoses. Discovering new therapeutic agents with low toxicity that produce better outcomes in patients with MCL is an ongoing challenge. Recent studies showed that degrasyn, a novel small-molecule inhibitor of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway, exerts antitumor activity in lymphoid tumors by inhibiting key growth and survival signaling (JAK/STAT) pathways. In the present study, we found that treatment of both typical and blastoid-variant MCL cells with degrasyn in combination with bortezomib resulted in synergistic growth inhibition and apoptosis induction in vitro. The apoptosis in these cells was correlated with the downregulation of constitutive NF-kappaB and phosphorylated STAT3 activation, leading to the inhibition of c-Myc, cyclin D1, and bcl-2 protein expression and the upregulation of bax protein expression. In vivo, degrasyn and bortezomib interacted to synergistically prevent tumor development and prolong survival durations in a xenotransplant severe combined immunodeficient mouse model of MCL. These findings suggest that agents such as degrasyn that can pharmacologically target constitutively expressed NF-kappaB and STAT3 in MCL cells may be useful therapeutic agents for MCL when administered together with bortezomib.
Pham
Lan V
LV
Department of Hematopathology, Unit 54, The University of Texas of M. D. Anderson Cancer Center, Houston, Texas 77030, USA. lvpham@mdanderson.org
Tamayo
Archito T
AT
Li
Changping
C
Bornmann
William
W
Priebe
Waldemar
W
Ford
Richard J
RJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003487:Cyanoacrylates; D019938:Cyclin D1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D003487:Cyanoacrylates; C489427:MYC protein, human; D016328:NF-kappa B; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C519751:degrasyn; D019938:Cyclin D1; D000069286:Bortezomib