Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Int J Oncol. 2023 Nov;63(5). doi: 10.3892/ijo.2023.5576. Epub 2023 Oct 6.
T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ‑secretase. γ‑secretase inhibitors (GSIs) are a NOTCH‑targeted therapy for T‑ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ‑secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH‑associated T‑ALL. The present study assessed the efficacy of nelfinavir against T‑ALL cells and investigated mechanisms of action and in preclinical treatment studies using a transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ‑secretase activity as well as the NOTCH1 pathway, thus suppressing T‑ALL cell viability. Additionally, microarray analysis of nelfinavir‑treated T‑ALL cells showed that nelfinavir upregulated mRNA levels of (glutathione‑specific γ‑glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T‑ALL cells. Moreover, nelfinavir suppressed mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating mRNA expression, upregulating and suppressing γ‑secretase via presenilin 1 inhibition and the mTOR pathway by upregulating via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.
T 细胞急性淋巴细胞白血病（T-ALL）是一种来源于 T 细胞谱系定向淋巴母细胞的肿瘤，其特征在于遗传改变导致致癌转录因子的激活和 NOTCH1 途径的激活。NOTCH 是一种通过 γ-分泌酶激活的跨膜受体蛋白。γ-分泌酶抑制剂（GSIs）是 T-ALL 的一种 NOTCH 靶向治疗药物。然而，由于不良反应（主要是胃肠道毒性）、疗效有限以及几种机制引起的耐药性，包括 AKT/mTOR 途径的激活，其临床应用并未成功。奈非那韦是一种人类免疫缺陷病毒 1 天冬氨酸蛋白酶抑制剂，已被重新用于抗癌药物。它通过诱导内质网（ER）应激和抑制 AKT/mTOR 途径发挥作用。因此，人们假设奈非那韦可能通过 γ-分泌酶抑制和阻断天冬氨酸蛋白酶早老素来抑制 NOTCH 途径，从而使奈非那韦对 NOTCH 相关 T-ALL 有效。本研究评估了奈非那韦对 T-ALL 细胞的疗效，并通过使用转基因小鼠模型进行了临床前治疗研究，探讨了作用机制。奈非那韦阻断早老素 1 加工并抑制 γ-分泌酶活性和 NOTCH1 途径，从而抑制 T-ALL 细胞活力。此外，奈非那韦处理的 T-ALL 细胞的微阵列分析显示，奈非那韦上调了 （谷胱甘肽特异性 γ-谷氨酰环转移酶 1，NOTCH 的负调节剂）和 sestrin 2 的 mRNA 水平（；mTOR 的负调节剂）。由于这两个因素都被 ER 应激上调，这证实了奈非那韦在 T-ALL 细胞中诱导了 ER 应激。此外，奈非那韦在微阵列分析中抑制了 mRNA 的表达。这些发现表明，奈非那韦通过下调 mRNA 的表达抑制 NOTCH1 途径，通过抑制早老素 1 和 mTOR 途径通过上调 来抑制 γ-分泌酶，通过诱导 ER 应激来上调 。此外，奈非那韦在 转基因小鼠模型中对 T-ALL 具有治疗效果。总的来说，这些发现强调了奈非那韦作为治疗 T-ALL 患者的新型治疗候选药物的潜力。
