The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs.
Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the U.S. The course of the disease has been shown to be negatively impacted by increased levels of BCL2. Strategies to downregulate BCL2 and shift the balance towards cellular demise are actively being explored. Therefore, we examined whether the investigational agent MLN2238 could inhibit the proteasomal machinery and induce CLL cell death while also downregulating BCL2. MLN2238-induced cell death was studied in peripheral blood mononuclear cells from 28 CLL patients. MLN2238 produced a dose-dependent reduction in BCL2 and CLL cell viability with maximum cell death observed at a 50 nmol/l concentration by 48 h. Annexin-V staining, PARP1 and caspase-3 cleavage along with an increase in mitochondrial membrane permeability were noted after cells were treated with MLN2238; however, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD.fmk. Furthermore, we observed enhanced anti-CLL effects in tumour cells treated with either a combination of MLN2238 and the BH3 mimetic AT-101 or MLN2238 and fludarabine. Together, our data suggest the potential for proteasome inhibitor based therapy in CLL and the rationale design of drug combination strategies based on CLL biology.
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
Aneel
A
Paulus
Aisha
A
Masood
Kena C
KC
Miller
A N M Nazmul H
AN
Khan
Drusilla
D
Akhtar
Pooja
P
Advani
James
J
Foran
Candido
C
Rivera
Vivek
V
Roy
Gerardo
G
Colon-Otero
Kasyapa
K
Chitta
Asher
A
Chanan-Khan
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001896:Boron Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009367:Neoplasm Staging; D010539:Permeability / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D001896:Boron Compounds; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C548400:ixazomib; D003907:Dexamethasone; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex; D014740:Vidarabine; D006072:Gossypol; C024352:fludarabine; C028178:gossypol acetic acid; D005998:Glycine
AT-101; CLL; Ixazomib; MLN2238; MLN9708