Abstract
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.
Highlights
Pancreatic cancer is characterized by an aggressive behavior and a poor response to chemotherapies to which contribute the activating mutations of proto-oncogenes and/or the inactivating mutations of tumor-suppressor genes that frequently occur in this cancer [1].Among the latter, there are mutations of the p53 gene that often affect its DNA-binding domain
We investigate whether the cytotoxic effect previously shown to be induced by valproic acid (VPA) and Trichostatin A (TSA) against pancreatic cancer cells [18]
We explored the impact of the HDAC inhibitors (HDACi)/AZD2461 combination on DNA damage
Summary
Pancreatic cancer is characterized by an aggressive behavior and a poor response to chemotherapies to which contribute the activating mutations of proto-oncogenes and/or the inactivating mutations of tumor-suppressor genes that frequently occur in this cancer [1].Among the latter, there are mutations of the p53 gene that often affect its DNA-binding domain. Pancreatic cancer is characterized by an aggressive behavior and a poor response to chemotherapies to which contribute the activating mutations of proto-oncogenes and/or the inactivating mutations of tumor-suppressor genes that frequently occur in this cancer [1]. In some cases, the presence of mutp may turn out to be an Achilles’s heel, as, for example, the R273H p53 mutation has been reported to render breast cancer cells more susceptible to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors [3] Regarding this topic, there are contradictory studies, including our own performed on colon cancer, which suggests that mutp could counteract the cytotoxicity of PARP inhibitors rather than increase it [4] or not influence the PARP inhibitor treatment at all [5]. It seems that, depending on the specific cellular contexts, mutp may differently influence the response of cancer cells to PARP inhibitor treatment
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