TY - JOUR
T1 - Preclinical activity of 8-chloroadenosine with mantle cell lymphoma
T2 - Roles of energy depletion and inhibition of DNA and RNA synthesis
AU - Dennison, Jennifer B.
AU - Balakrishnan, Kumudha
AU - Gandhi, Varsha
PY - 2009/11
Y1 - 2009/11
N2 - 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.
AB - 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.
KW - 8-chloroadenosine
KW - ATP
KW - DATP
KW - Mantle cell lymphoma
UR - http://www.scopus.com/inward/record.url?scp=70349925289&partnerID=8YFLogxK
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U2 - 10.1111/j.1365-2141.2009.07850.x
DO - 10.1111/j.1365-2141.2009.07850.x
M3 - Article
C2 - 19709085
AN - SCOPUS:70349925289
SN - 0007-1048
VL - 147
SP - 297
EP - 307
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 3
ER -