Co-targeting poly(ADP-ribose) polymerase (PARP) and histone deacetylase (HDAC) in triple-negative breast cancer: Higher synergism in BRCA mutated cells

奥拉帕尼 癌症研究 PARP抑制剂 三阴性乳腺癌 组蛋白脱乙酰基酶 聚ADP核糖聚合酶 组蛋白脱乙酰酶抑制剂 合成致死 DNA损伤 DNA修复 生物 化学 癌症 乳腺癌 医学 组蛋白 聚合酶 内科学 DNA 生物化学
作者
Hélène Marijon,Der‐Horng Lee,Ling‐Wen Ding,Haibo Sun,Sigal Gery,Aimery de Gramont,H. Phillip Koeffler
出处
期刊:Biomedicine & Pharmacotherapy [Elsevier]
卷期号:99: 543-551 被引量:50
标识
DOI:10.1016/j.biopha.2018.01.045
摘要

Despite similarities with BRCA-mutated breast cancers, triple-negative breast cancers (TNBC) remain resistant to poly(ADP-ribose) polymerase (PARP) inhibitors as single agents. Histone deacetylase inhibitors (HDACi) can decrease expression of proteins involved in DNA repair. We thus hypothesized that a HDACi (suberoylanilide hydroxamic acid (SAHA) or belinostat) could sensitize TNBC to the PARP inhibitor olaparib. Human TNBC cells were co-treated with olaparib and either SAHA or belinostat, and their effects on survival, proliferation, cell cycle, apoptosis and DNA repair pathways were evaluated. Subcutaneous xenografts were used to determine the effect of the combination treatment in vivo. HDACi and olaparib synergistically inhibited proliferation of a panel of 8 TNBC cell lines in vitro and in nude mice harboring TNBC xenografts in vivo. We noted a weaker synergism in PTEN-deficient TNBC cells and a stronger synergism in BRCA1-mutated TNBC cells. In the BRCA1-mutated cell line HCC-1937, we observed a drastic decrease in the expression of proteins involved in homologous recombination (HR), leading to a large imbalance of the ratio P-H2AX/RAD51. In BRCA1 wild type (wt) cell lines, effect of the combination treatment relied on DNA damage-induced cell cycle arrest followed by induction of apoptosis. In summary, these results provide a preclinical rationale to combine a HDACi with a PARP inhibitor to reduce HR efficiency in TNBC and sensitize these aggressive tumors to PARP inhibition.
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