Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.

Q2 Medicine Oncotarget Pub Date : 2024-06-03 DOI:10.18632/oncotarget.28588
Benigno C Valdez, Apostolia M Tsimberidou, Bin Yuan, Yago Nieto, Mehmet A Baysal, Abhijit Chakraborty, Clark R Andersen, Borje S Andersson
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Abstract

Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.

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组蛋白去乙酰化酶和聚-ADP核糖聚合酶抑制剂与地西他滨在胰腺癌细胞中的协同细胞毒性:对新型疗法的启示
组蛋白去乙酰化酶抑制剂(HDACi)可以调节蛋白质的乙酰化状态,从而影响癌细胞表现出的基因组不稳定性。聚(ADP 核糖)聚合酶(PARP)抑制剂(PARPi)可直接影响蛋白质的聚(ADP-核糖)生成,这对 DNA 修复非常重要。地西他滨是一种核苷胞嘧啶类似物,当其磷酸化时,会与生长的 DNA 链结合,抑制甲基化,并通过使 DNA 上的 DNA 甲基转移酶失活和诱捕 DNA 甲基转移酶来诱导 DNA 损伤,从而激活转录沉默的 DNA 位点。我们在胰腺癌细胞系 BxPC-3 和 PL45(野生型 BRCA1 和 BRCA2)以及 Capan-1(突变型 BRCA2)中探索了 HDACi 和 PARPi +/- 地西他滨(低甲基化剂)的各种组合。HDACi(panobinostat 或 vorinostat)与 PARPi(talazoparib 或 olaparib)联用可对所有受试细胞株产生协同细胞毒性。加入地西他滨可进一步增强 HDACi 和 PARPi 的协同细胞毒性,引发细胞凋亡(表现为 caspase 3 和 PARP1 的裂解增加)。三药联合疗法(伏立诺司他、他拉唑帕利和地西他滨;伏立诺司他、奥拉帕利和地西他滨;帕诺比诺司他、他拉唑帕利和地西他滨;帕诺比诺司他、奥拉帕利和地西他滨)比单药诱导更多的DNA损伤(组蛋白2AX磷酸化增加),并损害DNA修复途径(ATM、BRCA1和ATRX蛋白水平降低)。3 种药物组合还改变了基因表达的表观遗传调控(NuRD 复合物亚基水平降低)。这是首次证明上述药物在胰腺癌细胞系中协同作用的研究,为设计个体化治疗方法提供了临床前数据,有望改善胰腺癌的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Oncotarget
Oncotarget Oncogenes-CELL BIOLOGY
CiteScore
6.60
自引率
0.00%
发文量
129
审稿时长
1.5 months
期刊介绍: Information not localized
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