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
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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