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
5052 - Identification of first-in-class, naturally occurring LAG3 checkpoint inhibitor
Presenter: Gennady Bratslavsky
Session: Poster Display session 1
Resources:
Abstract
5336 - Are Epigenetic therapies modifying sensitivity to conventional chemotherapy?
Presenter: Alexandra Bizot
Session: Poster Display session 1
Resources:
Abstract
5739 - Oncogenic mutations at the dimer interface of EGFR lead to formation of covalent homo-dimers and allosteric activation of the kinase domain: A mechanism which alters the selectivity profile of oncogenic EGFR.
Presenter: Elizabeth Buck
Session: Poster Display session 1
Resources:
Abstract
5492 - Basic selective estrogen receptor degraders (B-SERDs) in combination with novel BET inhibitors in ER+ breast cancer
Presenter: Rui Xiong
Session: Poster Display session 1
Resources:
Abstract
5965 - EPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer
Presenter: Ronan Le Moigne
Session: Poster Display session 1
Resources:
Abstract
3582 - AVID200 neutralizes TGF-beta1 and -beta3, the principal immunosuppressive TGF-beta isoforms overexpressed by tumors, and sensitizes tumors to immune checkpoint inhibitors.
Presenter: Tina Gruosso
Session: Poster Display session 1
Resources:
Abstract
1996 - High NAMPT expression and anti-tumor activity of NAMPT inhibitor in adult T-cell leukemia/lymphoma
Presenter: Tomohiro Kozako
Session: Poster Display session 1
Resources:
Abstract
4307 - TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers
Presenter: Alexander Drilon
Session: Poster Display session 1
Resources:
Abstract
4869 - In Vivo Evaluation of Cisplatin-loaded PEG-PCL Block Copolymeric Nanoparticles for Anticancer Drug Delivery
Presenter: Yingtzu Yen
Session: Poster Display session 1
Resources:
Abstract
5054 - Inhibition of Rspo-Wnt pathway Facilitates Checkpoint Blockade Therapy by anti-RSPO3 antibody (DBPR117)
Presenter: John Hsu
Session: Poster Display session 1
Resources:
Abstract