Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncotarget. 2024 Jun 3;15:361-373. doi: 10.18632/oncotarget.28588.
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.
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，影响癌细胞表现出的基因组不稳定性。多聚 (ADP 核糖) 聚合酶 (PARP) 抑制剂 (PARPi) 对蛋白质多聚 (ADP-核糖基) 化有直接影响，这对于 DNA 修复很重要。地西他滨是一种核苷胞嘧啶类似物，当磷酸化后掺入正在生长的 DNA 链中，通过失活并将 DNA 甲基转移酶捕获在 DNA 上，抑制甲基化并诱导 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）和 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）的组合在所有测试的细胞系中均产生协同细胞毒性。添加地西他滨进一步增加了与 HDACi 和 PARPi 协同的细胞毒性，引发细胞凋亡（通过增加 caspase 3 和 PARP1 的裂解来证明）。三药联合治疗（vorinostat、talazoparib 和地西他滨；vorinostat、olaparib 和地西他滨；panobinostat、talazoparib 和地西他滨；panobinostat、olaparib 和地西他滨）诱导的 DNA 损伤（组蛋白 2AX 磷酸化增加）比单个药物更多，并损害 DNA 修复途径（ATM、BRCA1 和 ATRX 蛋白水平降低）。三药联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）。这是第一项证明上述药物在胰腺癌细胞系中协同作用的研究，并提供了设计个体化治疗方法的临床前数据，有可能改善胰腺癌治疗结果。
