Preclinical activity of 8-chloroadenosine with mantle cell lymphoma: Roles of energy depletion and inhibition of DNA and RNA synthesis

Abstract

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%, r2 = 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. © 2009 Blackwell Publishing Ltd.