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PI3K 抑制增强了 3a-氮杂环戊[α]茚衍生物在肺癌细胞中的治疗效果。

PI3K Inhibition Augments the Therapeutic Efficacy of a 3a-aza-Cyclopenta[α]indene Derivative in Lung Cancer Cells.

机构信息

Molecular Medicine Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.

Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

出版信息

Transl Oncol. 2014 Apr;7(2):256-266.e5. doi: 10.1016/j.tranon.2014.02.012. Epub 2014 Mar 4.

DOI:10.1016/j.tranon.2014.02.012
PMID:24913674
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4101349/
Abstract

The synergistic targeting of DNA damage and DNA repair is a promising strategy for the development of new chemotherapeutic agents for human lung cancer. The DNA interstrand cross-linking agent BO-1509, a derivative of 3a-aza-cyclopenta[α]indene, was synthesized and combined with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 to treat human lung cancer cells. Our results showed that the BO-1509 and LY294002 combination synergistically killed lung cancer cells in culture and also suppressed the growth of lung cancer xenografts in mice, including those derived from gefitinib-resistant cells. We also found that LY294002 suppressed the induction of several DNA repair proteins by BO-1509 and inhibited the nuclear translocation of Rad51. On the basis of the results of the γH2AX foci formation assays, LY294002 apparently inhibited the repair of DNA damage that was induced by BO-1509. According to the complete blood profile, biochemical enzyme analysis, and histopathologic analysis of major organs, no apparent toxicity was observed in mice treated with BO-1509 alone or in combination with LY294002. Our results suggest that the combination of a DNA cross-linking agent with a PI3K inhibitor is a feasible strategy for the treatment of patients with lung cancer.

摘要

协同靶向 DNA 损伤和 DNA 修复是开发人类肺癌新化疗药物的有前途的策略。DNA 链间交联剂 BO-1509 是 3a-氮杂环戊[α]茚的衍生物，已被合成并与磷酸肌醇 3-激酶 (PI3K) 抑制剂 LY294002 联合用于治疗人类肺癌细胞。我们的结果表明，BO-1509 和 LY294002 联合协同杀伤培养的肺癌细胞，并抑制小鼠肺癌异种移植物的生长，包括来自吉非替尼耐药细胞的异种移植物。我们还发现 LY294002 抑制了 BO-1509 诱导的几种 DNA 修复蛋白的诱导，并抑制了 Rad51 的核易位。基于 γH2AX 焦点形成测定的结果，LY294002 明显抑制了 BO-1509 诱导的 DNA 损伤修复。根据全血概况、生化酶分析和主要器官的组织病理学分析，单独使用 BO-1509 或与 LY294002 联合使用的小鼠未观察到明显的毒性。我们的结果表明，将 DNA 交联剂与 PI3K 抑制剂联合使用是治疗肺癌患者的可行策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/9145c914c579/fx5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/30f8202a08da/gr1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/2dc2331ba06f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/8ccaa37d7a29/gr5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/cafb88ca07fa/fx2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/90c6ccf9d2db/fx3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/0893357e36d9/fx4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/9145c914c579/fx5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/30f8202a08da/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/36a242562840/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/938880049b0d/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/2dc2331ba06f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/8ccaa37d7a29/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/f3158039c4f2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/e5262bf2af55/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/ca8d1454a378/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/cafb88ca07fa/fx2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/90c6ccf9d2db/fx3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/0893357e36d9/fx4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b63/4101349/9145c914c579/fx5.jpg

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