Abstract
Background:
HTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T-cell leukemia/lymphoma (ATLL). A major obstacle for effective treatment of ATLL resides in the genetic diversity of tumor cells and their ability to acquire resistance to chemotherapy regimens. As a result, most patients relapse and current therapeutic approaches still have limited long-term survival benefits. Hence, the development of novel approaches is greatly needed.
Methods:
In this study, we found that a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), PJ-34, is very effective in activating S/G2M cell cycle checkpoints, resulting in permanent cell cycle arrest and reactivation of p53 transcription functions and caspase-3-dependent apoptosis of HTLV-I-transformed and patient-derived ATLL tumor cells. We also found that HTLV-I-transformed MT-2 cells are resistant to PJ-34 therapy associated with reduced cleaved caspase-3 activation and increased expression of RelA/p65.
Conclusion:
Since PJ-34 has been tested in clinical trials for the treatment of solid tumors, our results suggest that some ATLL patients may be good candidates to benefit from PJ-34 therapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Apoptosis / drug effects*
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Apoptosis / genetics
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Blotting, Western
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Caspase 3 / metabolism
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Cell Cycle Checkpoints / drug effects*
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cyclin B1 / metabolism
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Leukemia-Lymphoma, Adult T-Cell / genetics
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Leukemia-Lymphoma, Adult T-Cell / pathology
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Phenanthrenes / pharmacology*
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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Tumor Suppressor Protein p53 / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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BAX protein, human
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Cyclin B1
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N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
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Phenanthrenes
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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RELA protein, human
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Transcription Factor RelA
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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Poly(ADP-ribose) Polymerases
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Caspase 3