Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells.

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.

• 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)

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

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)