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Preclinical activity of 8‐chloroadenosine with mantle cell lymphoma: roles of energy depletion and inhibition of DNA and RNA synthesis
Author(s) -
Dennison Jennifer B.,
Balakrishnan Kumudha,
Gandhi Varsha
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07850.x
Subject(s) - mantle cell lymphoma , microbiology and biotechnology , cyclin d1 , biology , cell culture , intracellular , programmed cell death , transcription (linguistics) , chemistry , cell , biochemistry , apoptosis , cell cycle , lymphoma , genetics , immunology , philosophy , linguistics
Summary 8‐Chloroadenosine (8‐Cl‐Ado), an RNA‐directed nucleoside analogue, is currently under evaluation in phase I clinical trials for treatment of chronic lymphocytic leukaemia. In the current study, the efficacy of 8‐Cl‐Ado was evaluated using mantle cell lymphoma (MCL) cell lines: Granta 519, JeKo, Mino, and SP‐53. After continuous exposure to 10 μmol/l 8‐Cl‐Ado for 24 h, loss of mitochondrial transmembrane potential and poly [adenosine diphosphate (ADP)‐ribose] polymerase (PARP) cleavage were detected in three of four cell lines. Reduced ATP levels (30–60% reduction) and concurrent 8‐Cl‐ATP accumulation were highly associated with cell death ( P < 0·01). The intracellular 8‐Cl‐ATP concentrations were also highly correlated with inhibition of global transcription (50–90%, r 2 = 0·90, P < 0·01). However, the inhibition of transcription only accounted for 30–40% of cell death as determined by equivalent inhibition with actinomycin D. Likewise, short‐lived mRNAs, those encoding cyclin D1 and Mcl‐1, were not consistently reduced after treatment. Unique to MCL as compared to other haematological malignancies, 8‐Cl‐Ado inhibited the rates of DNA synthesis and selectively depleted dATP pools (50–80%). We conclude that the DNA and RNA directed actions of 8‐Cl‐Ado in combination with depleted energetics may promote cell death and inhibit growth of MCL cell lines.