The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and differentiation. Notch1, a member of the Notch family, is implicated in many types of cancer, including breast cancer (especially triple-negative breast cancer), leukemias, brain tumors, and many others. Notch1 is tightly connected to many signaling pathways that are therapeutically involved in tumorigenesis. Together, they impact apoptosis, proliferation, chemosensitivity, immune response, and the population of cancer stem cells. Notch1 inhibition can be achieved through various and diverse methods, the most common of which are the γ-secretase inhibitors, which produce a pan-Notch inhibition, or the use of Notch1 short interference RNA or Notch1 monoclonal antibodies, which produce a more specific blockade. Downregulation of Notch1 can be used alone or in combination with chemotherapy, which can achieve a synergistic effect and a decrease in chemoresistance. Targeting Notch1 in cancers that harbor high expression levels of Notch1 offers an addition to therapeutic strategies recruited for managing cancer. Considering available evidence, Notch1 offers a legitimate target that might be incorporated in future strategies for combating cancer. In this review, the possible clinical applications of Notch1 inhibition and the obstacles that hinder its clinical application are discussed.

中文翻译：

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癌症治疗中的Notch 1：可能的临床意义和挑战。

Notch家族由四个高度保守的跨膜受体组成。活性细胞内结构域的释放需要γ的酶促活性-分泌酶。Notch参与胚胎发育和正常细胞的许多生理过程，在其中调节生长，凋亡和分化。Notch1是Notch家族的成员，与多种类型的癌症有关，包括乳腺癌（尤其是三阴性乳腺癌），白血病，脑瘤等。Notch1与许多与肿瘤发生有关的信号通路紧密相连。它们共同影响细胞凋亡，增殖，化学敏感性，免疫反应和癌症干细胞的数量。Notch1抑制可通过多种方法来实现，其中最常见的是γ-分泌酶抑制剂可产生泛Notch抑制作用，或使用Notch1短干扰RNA或Notch1单克隆抗体可产生更特异性的阻断作用。Notch1的下调可以单独使用，也可以与化学疗法结合使用，可以达到协同作用并降低化学耐药性。在具有高表达水平的Notch1的癌症中靶向Notch1为招募用于治疗癌症的治疗策略提供了新的内容。考虑到现有证据，Notch1提供了一个合理的目标，可以将其纳入未来的抗癌策略中。在这篇综述中，讨论了Notch1抑制作用的可能的临床应用以及阻碍其临床应用的障碍。