PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells.
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Bhalla S, Balasubramanian S, David K, Sirisawad M, Buggy J, Mauro L, Prachand S, Miller R, Gordon LI, Evens AM
PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells.
Clin Cancer Res. 2009 May 15;15(10):3354-65. doi: 10.1158/1078-0432.CCR-08-2365. Epub 2009 May 5.
- PubMed ID
- 19417023 [ View in PubMed]
- Abstract
PURPOSE: We investigated the cytotoxicity and mechanisms of cell death of the broad-spectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells. EXPERIMENTAL DESIGN: Apoptosis, mitochondrial membrane potential, cell cycle analysis, and reactive oxygen species (ROS) were measured by flow cytometry, whereas caspase activation was determined by Western blot. Nuclear factor kappaB (NF-kappaB)-related mRNAs were quantified by reverse transcription-PCR, NF-kappaB-related proteins by Western blotting, and NF-kappaB DNA-binding activity by electromobility shift assay. Finally, gene expression profiling was analyzed. RESULTS: PCI-24781 induced concentration-dependent apoptosis that was associated with prominent G(0)/G(1) arrest, decreased S-phase, increased p21 protein, and increased ROS in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Dose-dependent apoptosis with PCI-24781 was also seen among primary CLL/SLL cells. PCI-24781-induced apoptosis was shown to be ROS- and caspase-dependent. Combined PCI-24781/bortezomib treatment resulted in strong synergistic apoptosis in all non-Hodgkin lymphoma lines (combination indices, 0.19-0.6) and was additive in Hodgkin lymphoma and primary CLL/SLL cells. Further, PCI-24781/bortezomib resulted in increased caspase cleavage, mitochondrial depolarization, and histone acetylation compared with either agent alone. Gene expression profiling showed that PCI-24781 alone significantly down-regulated several antioxidant genes, proteasome components, and NF-kappaB pathway genes, effects that were enhanced further with bortezomib. Reverse transcription-PCR confirmed down-regulation of NF-kappaB1 (p105), c-Myc, and IkappaB-kinase subunits, where NF-kappaB DNA binding activity was decreased. CONCLUSION: We show that PCI-24781 results in increased ROS and NF-kappaB inhibition, leading to caspase-dependent apoptosis. We also show that bortezomib is synergistic with PCI-24781. This combination or PCI-24781 alone has potential therapeutic value in lymphoma.
DrugBank Data that Cites this Article
- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Abexinostat Investigational CCL3 6348 downregulated abexinostat results in decreased expression of CCL3 mRNA 17q12 Abexinostat Investigational CCL7 6354 downregulated abexinostat results in decreased expression of CCL7 mRNA 17q12 Abexinostat Investigational HMOX1 3162 upregulated abexinostat results in increased expression of HMOX1 mRNA 22q12.3 Abexinostat Investigational HMOX2 3163 downregulated abexinostat results in decreased expression of HMOX2 mRNA 16p13.3 Abexinostat Investigational IKBKB 3551 downregulated abexinostat results in decreased expression of IKBKB mRNA 8p11.21 Abexinostat Investigational NFKB1 4790 downregulated abexinostat results in decreased expression of NFKB1 mRNA 4q24 Abexinostat Investigational RELB 5971 downregulated abexinostat results in decreased expression of RELB mRNA 19q13.32 Abexinostat Investigational TXN2 25828 downregulated abexinostat results in decreased expression of TXN2 mRNA 22q12.3 Abexinostat Investigational TXNRD2 10587 downregulated abexinostat results in decreased expression of TXNRD2 mRNA 22q11.21