Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Blood. 2010 Dec 16;116(25):5622-30. doi: 10.1182/blood-2010-05-285866. Epub 2010 Sep 15.
8-Aminoadenosine (8-NH(2)-Ado), a ribosyl nucleoside analog, in preclinical models of multiple myeloma inhibits phosphorylation of proteins in multiple growth and survival pathways, including Akt. Given that Akt controls the activity of mammalian target of rapamycin (mTOR), we hypothesized that 8-NH(2)-Ado would be active in mantle cell lymphoma (MCL), a hematological malignancy clinically responsive to mTOR inhibitors. In the current study, the preclinical efficacy of 8-NH(2)-Ado and its resulting effects on Akt/mTOR and extracellular-signal-regulated kinase signaling were evaluated using 4 MCL cell lines, primary MCL cells, and normal lymphocytes from healthy donors. For all MCL cell lines, 8-NH(2)-Ado inhibited growth and promoted cell death as shown by reduction of thymidine incorporation, loss of mitochondrial membrane potential, and poly (adenosine diphosphate-ribose) polymerase cleavage. The efficacy of 8-NH(2)-Ado was highly associated with intracellular accumulation of 8-NH(2)-adenosine triphosphate (ATP) and loss of endogenous ATP. Formation of 8-NH(2)-ATP was also associated with inhibition of transcription and translation accompanied by loss of phosphorylated (p-)Akt, p-mTOR, p-Erk1/2, p-phosphoprotein (p)38, p-S6, and p-4E-binding protein 1. While normal lymphocytes accumulated 8-NH(2)-ATP but maintained their viability with 8-NH(2)-Ado treatment, primary lymphoma cells accumulated higher concentrations of 8-NH(2)-ATP, had increased loss of ATP, and underwent apoptosis. We conclude that 8-NH(2)-Ado is efficacious in preclinical models of MCL and inhibits signaling of Akt/mTOR and Erk pathways.
8-氨基腺嘌呤核苷（8-NH2-Ado）是一种核糖核苷类似物，在多发性骨髓瘤的临床前模型中可抑制包括 Akt 在内的多种生长和存活途径中的蛋白质磷酸化。鉴于 Akt 控制雷帕霉素（mTOR）的哺乳动物靶标（mTOR）的活性，我们假设 8-NH2-Ado 在套细胞淋巴瘤（MCL）中具有活性，MCL 是一种对 mTOR 抑制剂具有临床反应的血液恶性肿瘤。在本研究中，使用 4 种 MCL 细胞系、原代 MCL 细胞和来自健康供体的正常淋巴细胞，评估了 8-NH2-Ado 的临床前疗效及其对 Akt/mTOR 和细胞外信号调节激酶信号的影响。对于所有 MCL 细胞系，8-NH2-Ado 抑制生长并促进细胞死亡，表现为胸苷掺入减少、线粒体膜电位丧失和多聚（腺苷二磷酸核糖）聚合酶裂解。8-NH2-Ado 的疗效与 8-NH2-腺嘌呤三磷酸（8-NH2-ATP）的细胞内积累和内源性 ATP 的丧失高度相关。8-NH2-ATP 的形成也与转录和翻译的抑制以及磷酸化（p-）Akt、p-mTOR、p-Erk1/2、p-磷酸化蛋白（p）38、p-S6 和 p-4E 结合蛋白 1 的丧失相关。虽然正常淋巴细胞积累了 8-NH2-ATP，但在用 8-NH2-Ado 处理时仍保持其活力，但原代淋巴瘤细胞积累了更高浓度的 8-NH2-ATP，ATP 丢失增加，并发生凋亡。我们得出结论，8-NH2-Ado 在 MCL 的临床前模型中有效，并抑制 Akt/mTOR 和 Erk 途径的信号。
