The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs
Aneel Paulus
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Contributed equally to the study.Search for more papers by this authorAisha Masood
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
Department of Internal Medicine, State University of New York at Stony Brook University, Stony Brook, NY, USA
Contributed equally to the study.Search for more papers by this authorKena C. Miller
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorA. N. M. Nazmul H. Khan
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
Department of Infectious Diseases, Roswell Park Cancer Institute, Buffalo, NY, USA
Search for more papers by this authorDrusilla Akhtar
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
Search for more papers by this authorPooja Advani
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorJames Foran
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorCandido Rivera
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorVivek Roy
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorGerardo Colon-Otero
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorKasyapa Chitta
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorCorresponding Author
Asher Chanan-Khan
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Correspondence: Dr Asher Chanan-Khan, Division of Hematology & Oncology, Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
E-mail: [email protected]
Search for more papers by this authorAneel Paulus
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Contributed equally to the study.Search for more papers by this authorAisha Masood
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
Department of Internal Medicine, State University of New York at Stony Brook University, Stony Brook, NY, USA
Contributed equally to the study.Search for more papers by this authorKena C. Miller
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorA. N. M. Nazmul H. Khan
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
Department of Infectious Diseases, Roswell Park Cancer Institute, Buffalo, NY, USA
Search for more papers by this authorDrusilla Akhtar
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
Search for more papers by this authorPooja Advani
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorJames Foran
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorCandido Rivera
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorVivek Roy
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorGerardo Colon-Otero
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorKasyapa Chitta
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
Search for more papers by this authorCorresponding Author
Asher Chanan-Khan
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
Correspondence: Dr Asher Chanan-Khan, Division of Hematology & Oncology, Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
E-mail: [email protected]
Search for more papers by this authorSummary
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.
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