Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP.
Myeloid cell leukemia-1 (MCL-1) acts as a key survival factor for chronic lymphocytic leukemia (CLL) cells. In addition, dissipation of cellular bioenergy may impose a lethal effect on these quiescent cells. Previously, in multiple myeloma cell lines we demonstrated that halogenated adenosine (8-Cl-Ado) was phosphorylated to triphosphate (8-Cl-adenosine triphosphate [ATP]), which preferentially incorporated into mRNA and inhibited RNA synthesis by premature transcription termination. Furthermore, 8-Cl-ATP accumulation was associated with a decline in cellular bioenergy. Based on these actions, we hypothesized that 8-Cl-Ado would be ideal to target CLL lymphocytes. In the present study we demonstrate that leukemic lymphocytes incubated with 8-Cl-Ado display time- and dose-dependent increase in the accumulation of 8-Cl-ATP, with a parallel depletion of the endogenous ATP pool. Inhibition of global RNA synthesis resulted in a significant decline in the expression of transcripts with a short half-life such as MCL1. Consistent to this, protein expression of MCL-1 but not B-cell lymphoma-2 (BCL-2) was decreased. Furthermore, 8-Cl-ATP induced programmed cell death, as suggested by caspases activation, cleavage of caspase 3, and PARP (poly-adenosine diphosphate [ADP]-ribose polymerase), and increased DNA fragmentation. In conclusion, 8-Cl-Ado induces apoptosis in CLL lymphocytes by targeting cellular bioenergy as well as RNA transcription and translation of key survival genes such as MCL1.
Balakrishnan
Kumudha
K
Department of Experimental Therapeutics, Unit 71, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Stellrecht
Christine M
CM
Genini
Davide
D
Ayres
Mary
M
Wierda
William G
WG
Keating
Michael J
MJ
Leoni
Lorenzo M
LM
Gandhi
Varsha
V
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*
C465859:8-chloro-ATP; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000255:Adenosine Triphosphate
Cancer Res. 2001 Jul 15;61(14):5474-9
11454694
Semin Oncol. 1998 Feb;25(1):65-74
9482528
J Clin Oncol. 2001 Nov 15;19(22):4252-8
11709569
Blood. 2002 Feb 1;99(3):1038-43
11807010
Leukemia. 2002 Apr;16(4):444-54
11960321
Blood. 2002 Jul 1;100(1):194-9
12070027
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Nucleosides Nucleotides Nucleic Acids. 2002;21(8-9):599-617
12484453
Br J Haematol. 2003 Feb;120(3):434-41
12580957
J Clin Oncol. 2003 Apr 15;21(8):1466-71
12697868
Biochem Biophys Res Commun. 2003 May 9;304(3):437-44
12729577
Exp Cell Res. 2003 May 15;286(1):152-63
12729803
Rev Clin Exp Hematol. 2002 Dec;6(4):350-65; discussion 449-50
12823777
Cancer Res. 2003 Nov 15;63(22):7968-74
14633728
Nature. 2003 Dec 11;426(6967):671-6
14668867
Blood. 2004 Jan 15;103(2):375-82
14504108
J Biol Chem. 2004 Sep 24;279(39):40405-11
15265873
Cancer Res. 1980 Mar;40(3):588-91
6937239
J Clin Invest. 1985 Feb;75(2):377-83
2579098
Cancer Res. 1989 Oct 15;49(20):5650-5
2676146
Anticancer Drugs. 1992 Oct;3(5):485-91
1450443
EMBO J. 1994 Feb 1;13(3):683-91
8313913
Cancer Res. 1994 Dec 15;54(24):6348-52
7987827
J Cell Biol. 1995 Mar;128(6):1173-84
7896880
Am J Pathol. 1995 Jun;146(6):1309-19
7778670
Biochem Pharmacol. 1995 Nov 27;50(11):1943-8
8615876
J Cell Physiol. 1996 Mar;166(3):523-36
8600156
Leuk Res. 1996 Feb;20(2):109-11
8628008
Br J Haematol. 1996 Sep;94(4):612-8
8826882
Blood. 1997 Jan 15;89(2):630-43
9002967
Blood. 1998 May 1;91(9):3379-89
9558396
Mol Cell Biol. 1998 Aug;18(8):4883-98
9671497
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9567-71
9689121
Blood. 1998 Aug 15;92(4):1165-71
9694704
Ann Hematol. 1998 Jul-Aug;77(1-2):89-91
9760161
Blood. 1998 Oct 15;92(8):2893-8
9763575
Clin Cancer Res. 1997 Oct;3(10):1781-7
9815564
J Cell Physiol. 1999 Jul;180(1):71-80
10362019
Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13978-82
10570184
Endocrinology. 1999 Dec;140(12):5469-77
10579309
J Biol Chem. 2000 Jan 7;275(1):29-34
10617581
Curr Opin Oncol. 2000 Jan;12(1):22-9
10687725
Oncogene. 2000 Mar 23;19(13):1665-75
10763823
Blood. 2000 Jul 15;96(2):393-7
10887097
Blood. 2000 Jul 1;96(1):71-5
10891432
Blood. 2000 Sep 1;96(5):1756-63
10961874
J Chromatogr B Biomed Sci Appl. 2000 Aug 18;745(2):421-30
11043760
Blood. 2000 Nov 15;96(10):3537-43
11071652
J Clin Oncol. 2001 Mar 1;19(5):1414-20
11230486
Biochem J. 2001 Jun 1;356(Pt 2):473-80
11368774
Biochem Pharmacol. 1997 Jan 24;53(2):141-8
9037246
Br J Cancer. 1997;76(4):511-8
9275029
Blood. 1998 Feb 1;91(3):991-1000
9446661
Genome Biol. 2001;2(10):RESEARCH0041
11597333