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.
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Authors | Xue Tao Bai, Ramona Moles, Hassiba Chaib-Mezrag, Christophe Nicot |
Journal | Journal of hematology & oncology
(J Hematol Oncol)
Vol. 8
Pg. 117
(Oct 23 2015)
ISSN: 1756-8722 [Electronic] England |
PMID | 26497583
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- BAX protein, human
- Cyclin B1
- N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
- Phenanthrenes
- Poly(ADP-ribose) Polymerase Inhibitors
- Proto-Oncogene Proteins c-bcl-2
- RELA protein, human
- Transcription Factor RelA
- Tumor Suppressor Protein p53
- bcl-2-Associated X Protein
- Poly(ADP-ribose) Polymerases
- Caspase 3
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Topics |
- Adult
- Apoptosis
(drug effects, genetics)
- Blotting, Western
- Caspase 3
(metabolism)
- Cell Cycle Checkpoints
(drug effects, genetics)
- Cell Line, Tumor
- Cyclin B1
(metabolism)
- Drug Resistance, Neoplasm
(drug effects, genetics)
- Gene Expression Regulation, Leukemic
(drug effects)
- Humans
- Leukemia-Lymphoma, Adult T-Cell
(genetics, metabolism, pathology)
- Phenanthrenes
(pharmacology)
- Poly(ADP-ribose) Polymerase Inhibitors
(pharmacology)
- Poly(ADP-ribose) Polymerases
(genetics, metabolism)
- Proto-Oncogene Proteins c-bcl-2
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription Factor RelA
(genetics, metabolism)
- Tumor Suppressor Protein p53
(metabolism)
- bcl-2-Associated X Protein
(genetics, metabolism)
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