Abstract 3722
Background
Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by histone acetyltransferases (HAT) and histone deacetylases (HDAC). Recent studies have demonstrated that several chromatin-regulating proteins can modulate cellular responses to other cytotoxic modalities including ionizing radiation and chemotherapeutic drugs. Even though histone acetylation is one of the key mechanisms of epigenetic regulation, relatively little is known about the cancer therapeutic potential of HAT inhibitors. This is in stark contrast to the well-studied effects of HDAC inhibitors. In this study, we investigated the proton beam-sensitizing effect of C646, a selective small molecule inhibitor of p300 histone acetyltransferase in human pancreatic cancer cells.
Methods
Cell viability assay (CCK-8; Dojindo), Clonogenic survival assay, Cell cycle analysis (PI staining). Annexin V-FITC and PI staining, γ-H2AX foci, Western blot, BxPC-3 Xenograft tumor model, TUNEL assay.
Results
AsPC-1, BxPC-3 and Mia-paca2 cells exhibited increase in radiosensitivity when exposed to C646 at all doses of proton beam tested. C646 pre-treatment induce led to increase of sub-G1 population and abolishment of G2/M arrest. Flow cytometry analysis with annexin V staining and Western blot analysis showed that The pre-treatment with C646 significantly enhanced proton-induced apoptotic cell death through the down-regulation of anti-apoptotic molecules. Our in vivo results demonstrate synergistic effects of combination therapy with C646 and proton beam. In BxPC-3 xenograft tumor model, C646 pre-treatment increased proton-induced tumor growth inhibition and apoptotic cell death in tumor tissues. In addition, the combination treatment of C646 with proton beam increased DNA damage and decreased activation of DNA repair pathway compared with proton alone.
Conclusions
Our results suggest that the C646 may increase proton- induced apoptosis through the modulation of various pro- and anti- apoptotic molecules in human pancreatic cancer cells. These results provide proof of principle that the inhibition of histone acetylation by HATis can be exploited to develop new proton-sensitizer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Research Foundation of Korea (NRF).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4852 - Impact of routine screening and preemptive treatment on hepatitis B virus reactivation (HBVr) in patients receiving chemotherapy
Presenter: Celine Marty
Session: Poster Display session 1
Resources:
Abstract
5225 - The uptake, patient satisfaction and efficacy of scalp cooling among patients receiving chemotherapy in an Irish oncology day ward.
Presenter: William Maher
Session: Poster Display session 1
Resources:
Abstract
1901 - Placebo adverse events (AEs) in targeted and immune cancer therapy in the adjuvant and advanced setting: A systematic review and meta-analysis
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract
3258 - Reduced antibody levels and high seronegativity rates against vaccine preventable diseases pose a risk factor for infections in patients with solid and hematologic cancers
Presenter: Angela Guzek
Session: Poster Display session 1
Resources:
Abstract
3211 - Prognostic Factors Influencing Outcome After Therapy With Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin's Lymphoma
Presenter: Veselina Goranova - Marinova
Session: Poster Display session 1
Resources:
Abstract
4949 - Phase I Study of CC-90010 in Patients With Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL)
Presenter: Victor Moreno
Session: Poster Display session 1
Resources:
Abstract
2271 - Pretreatment coagulation factors related to prognosis in patients with natural killer/T cell lymphoma
Presenter: Yue Chai
Session: Poster Display session 1
Resources:
Abstract
4335 - Diffuse large B cell lymphoma in the elderly. A retrospective analysis of standard versus alternative treatments
Presenter: Irene Sillero
Session: Poster Display session 1
Resources:
Abstract
5117 - MIPI as a superior prognostic tool in Mantle Cell Lymphoma compared to monocyte-lymphocyte, neutrophil-lymphocyte and platelet-lymphocyte ratios
Presenter: Filipa Macedo
Session: Poster Display session 1
Resources:
Abstract
5135 - Dose adjustment of chemotherapy in aggressive lymphoma using automated and standardized analysis and evaluation of DNA double strand breaks
Presenter: Julia Schröder
Session: Poster Display session 1
Resources:
Abstract