The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer
文献类型：期刊论文
| 作者 | Ma, Liying1,2,3; Bian, Xing1,2,3; Lin, Wenchu1,3 |
| 刊名 | JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
 |
| 出版日期 | 2020-10-17 |
| 卷号 | 39 |
| 关键词 | SCLC PI3K HDAC CUDC-907 PARP1 Olaparib DSB repair Combination treatment |
| DOI | 10.1186/s13046-020-01728-2 |
| 通讯作者 | Lin, Wenchu(wenchu@hmfl.ac.cn) |
| 英文摘要 | Background Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor with limited therapeutic options. Recent data suggest that histone deacetylases (HDACs) and the phosphatidylinositol 3-kinase (PI3K) pathway play essential roles in SCLC cell proliferation and survival. Methods The inhibition of the PI3K signaling and HDAC activity by CUDC-907 was analyzed by western blotting. The effect of CUDC-907 on olaparib-induced DNA damage response was assessed by western blotting and Immunofluorescence staining. The cytotoxicity of CUDC-907 alone or in combination with olaparib in a panel of SCLC cell lines were evaluated by the CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. The in vivo effects of CUDC-907 and olaparib alone or in combination were examined using a patient-derived xenografts (PDX) model of SCLC. Results CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell-cycle arrest, and impaired DNA double-strand break (DSB) repair capacity in SCLC cells, which produced a potent antiproliferative effect. Furthermore, we showed that CUDC-907 treatment enhanced the therapeutic efficacy of PARP inhibitor olaparib in SCLC cellular models and a PDX model. Mechanistic investigations demonstrated that CUDC-907 synergized with olaparib through the blockade of DSB repair pathways and downregulation of MYC paralogs and FoxM1. Conclusions Our study uncovers that dual PI3K and HDAC inhibition by CUDC-907 exerts significant single-agent activity and strong synergistic effects with PARP inhibitor olaparib in SCLC, which thus provides a rational combination treatment strategy for SCLC clinical investigation. |
| WOS关键词 | HDAC ; PATHWAY ; GROWTH ; MYC ; ROMIDEPSIN ; LYMPHOMA ; RAD001 ; DEATH |
| 资助项目 | National Natural Science Foundation of China[81972191] ; National Natural Science Foundation of China[81672647] ; Science and Technology Major Project of Anhui Province[18030801140] ; Key program of 13th five-year plan of CASHIPS[KP-2017-26] ; 100-Talent Program of Chinese Academy of Sciences ; High Magnetic Field Laboratory of Anhui Province |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000579306300001 |
| 出版者 | BMC |
| 资助机构 | National Natural Science Foundation of China ; Science and Technology Major Project of Anhui Province ; Key program of 13th five-year plan of CASHIPS ; 100-Talent Program of Chinese Academy of Sciences ; High Magnetic Field Laboratory of Anhui Province |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/104681]  |
| 专题 | 中国科学院合肥物质科学研究院 |
| 通讯作者 | Lin, Wenchu |
| 作者单位 | 1.Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China 3.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Anhui, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Liying,Bian, Xing,Lin, Wenchu. The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer[J]. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2020,39. |
| APA | Ma, Liying,Bian, Xing,&Lin, Wenchu.(2020).The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,39. |
| MLA | Ma, Liying,et al."The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 39(2020). |
入库方式： OAI收割
来源：合肥物质科学研究院
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