Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms23042268
Keywords
pancreatic cancer; HDACi; PARPi; mutp53; HSP70; RAD51; CHK1
Funding
- Istituto Pasteur Italia, Fondazione Cenci Bolognetti, PRIN 2017 [2017K55HLC]
- PRIN 2020 [20205HZBP-8_006)]
- Italian Association for Cancer Research (AIRC) [23040]
- ATENEO 2019
- [20205HZBP-8_006]
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The combination of HDAC inhibitors and PARP inhibitors may improve the treatment of pancreatic cancer, which is a highly aggressive and therapy-resistant cancer.
HDAC inhibitors (HDACi) represent promising anti-cancer treatments, as the acetylation of histone and non-histone proteins is often dysregulated in cancer and contributes to cancer onset and progression. HDACi have been also reported to increase the cytotoxicity of DNA-damaging agents, such as radiation or cisplatin. In this study, we found that TSA and, even more effectively, VPA synergized with AZD2461, PARP1, 2 and 3 inhibitor (PARPi) to induce DNA damage and reduce pancreatic cancer cell survival. At a molecular level, VPA and TSA down-regulated CHK1 and RAD51, which is correlated with the interruption of the cross-talk between mutp53 and HSP70. Moreover, VPA and to a lesser extent TSA reactivated wtp53 in these cells, which contributed to CHK1 and RAD51 reduction. These findings suggest that the combination of HDACi and PARPi might improve the treatment of pancreatic cancer, which remains one of the most aggressive and therapy-resistant cancers.
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