The brain-penetrant cell-cycle inhibitor p28 sensitizes brain metastases to DNA-damaging agents.
The brain-penetrant cell-cycle inhibitor p28 sensitizes brain metastases to DNA-damaging agents.
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DOI：
10.1093/noajnl/vdad042
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发表时间：
2023-01
期刊：
影响因子：
--
通讯作者：
Yamada, Tohru
中科院分区：
文献类型：
--
作者：
Mander, Sunam;Gorman, Gregory S.;Coward, Lori U.;Christov, Konstantin;Green, Albert;Das Gupta, Tapas K.;Yamada, Tohru
脑转移瘤（BM）是中枢神经系统最常见的肿瘤，预后不良，危及生命。开发有效治疗BM的主要挑战是药物靶向肿瘤和穿过血脑屏障（BBB）的能力有限。我们的目的是研究我们的治疗方法对小鼠模型中BM的疗效，这些模型概括了BM的临床表现。通过心内注射人乳腺癌、肺癌和黑色素瘤来构建BM小鼠模型，这使得BBB保持完整。我们研究了细胞穿透肽p28在体外3D模型和BM动物模型中穿过BBB的能力。还评估了p28与DNA损伤剂（辐射和替莫唑胺）组合对BM的治疗效果。p28比标准化疗剂替莫唑胺更有效地穿过完整的BBB。在穿过血脑屏障后，p28优先定位于肿瘤病变，并通过激活p53-p21轴增强DNA损伤剂的功效。在BM动物模型中，辐射与p28的组合显著降低了BM的肿瘤负荷。细胞周期抑制剂p28可以穿过血脑屏障定位于脑中的肿瘤病变，并增强DNA损伤剂对BM的抑制作用，表明该分子在BM中的潜在治疗益处。
Brain metastases (BMs), the most common tumors of the central nervous system, are life-threatening with a dismal prognosis. The major challenges to developing effective treatments for BMs are the limited abilities of drugs to target tumors and to cross the blood-brain barrier (BBB). We aimed to investigate the efficacy of our therapeutic approach against BMs in mouse models that recapitulate the clinical manifestations of BMs. BMs mouse models were constructed by injecting human breast, lung cancer, and melanoma intracardially, which allowed the BBB to remain intact. We investigated the ability of the cell-penetrating peptide p28 to cross the BBB in an in vitro 3D model and in the BMs animal models. The therapeutic effects of p28 in combination with DNA-damaging agents (radiation and temozolomide) on BMs were also evaluated. p28 crossed the intact BBB more efficiently than the standard chemotherapeutic agent, temozolomide. Upon crossing the BBB, p28 localized preferentially to tumor lesions and enhanced the efficacy of DNA-damaging agents by activating the p53-p21 axis. In the BMs animal models, radiation in combination with p28 significantly reduced the tumor burden of BMs. The cell-cycle inhibitor p28 can cross the BBB localize to tumor lesions in the brain and enhance the inhibitory effects of DNA-damaging agents on BMs, suggesting the potential therapeutic benefits of this molecule in BMs.
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