British Journal of Haematology 2014-04-01

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, Aisha Masood, Kena C Miller, A N M Nazmul H Khan, Drusilla Akhtar, Pooja Advani, James Foran, Candido Rivera, Vivek Roy, Gerardo Colon-Otero, Kasyapa Chitta, Asher Chanan-Khan

Index: Br. J. Haematol. 165(1) , 78-88, (2014)

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Abstract

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. © 2014 John Wiley & Sons Ltd.