聚腺苷二磷酸核糖聚合酶抑制剂奥拉帕尼增强了骨肉瘤中 DNA 损伤药物阿霉素的作用。
The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma.
机构信息
Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea.
Department of Orthopedic Surgery, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea.
出版信息
J Exp Clin Cancer Res. 2018 May 21;37(1):107. doi: 10.1186/s13046-018-0772-9.
BACKGROUND
PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as γH2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma.
METHODS
We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells.
RESULTS
The expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with shorter survival of osteosarcoma patients. In osteosarcoma cells, knock-down of PARP1 and treatment of olaparib significantly inhibited proliferation of cells and induced apoptosis. Moreover, the anti-tumor effect was more significant with co-treatment of olaparib and doxorubicin in vitro and in vivo.
CONCLUSIONS
This study suggests that combined use of a PARP inhibitor with doxorubicin, a DNA damaging agent, might be effective in the treatment of osteosarcoma patients, especially in the poor-prognostic subgroups of osteosarcoma expressing PARP1, γH2AX, or BRCA1/2.
背景
PARP1 通过招募 DNA 损伤反应分子（如 γH2AX 和 BRCA1/2）来促进受损 DNA 细胞的恢复，并且在抗肿瘤治疗的耐药性中发挥作用。因此，PARP 抑制被评估为一种抗癌疗法。然而，关于 PARP 抑制在骨肉瘤中的研究有限。
方法
我们评估了 35 个人骨肉瘤中 DNA 损伤反应分子的表达，并研究了 PARP 抑制剂奥拉帕尼与多柔比星联合治疗骨肉瘤细胞的效果。
结果
PARP1、γH2AX、BRCA1 和 BRCA2 的表达模式与骨肉瘤患者的生存时间显著相关。在骨肉瘤细胞中，PARP1 的敲低和奥拉帕尼的治疗显著抑制了细胞的增殖并诱导了细胞凋亡。此外，奥拉帕尼与多柔比星联合治疗在体外和体内均具有更显著的抗肿瘤作用。
结论
本研究表明，PARP 抑制剂与多柔比星（一种 DNA 损伤剂）联合使用可能对骨肉瘤患者，特别是表达 PARP1、γH2AX 或 BRCA1/2 的骨肉瘤预后不良亚组患者的治疗有效。
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