Institute of Microbial Chemistry, Numazu, Japan.
Cancer Sci. 2014 Dec;105(12):1609-15. doi: 10.1111/cas.12542. Epub 2014 Oct 21.
The proteasome degrades numerous regulatory proteins that are critical for tumor growth. Thus, proteasome inhibitors are promising antitumor agents. New proteasome inhibitors, such as tyropeptins and tyropeptin-boronic acid derivatives, have a potent inhibitory activity. Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29. AS-06 and AS-29 significantly suppress the degradation of the proteasome-sensitive fluorescent proteins in HEK293PS cells, and induce the accumulation of ubiquitinated proteins in human multiple myeloma cells. We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation. Furthermore, we demonstrate that AS-06 and AS-29 induce apoptosis through the caspase-8 and caspase-9 cascades. In a xenograft mouse model, i.v. administration of tyropeptin-boronic acid derivatives inhibits proteasome in tumors and clearly suppresses tumor growth in mice bearing human multiple myeloma. Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.
蛋白酶体降解许多对肿瘤生长至关重要的调节蛋白。因此，蛋白酶体抑制剂是很有前途的抗肿瘤药物。新型蛋白酶体抑制剂，如酪蛋白肽和酪蛋白肽硼酸衍生物，具有很强的抑制活性。在这里，我们报告了两种新型酪蛋白肽硼酸衍生物 AS-06 和 AS-29 的抗肿瘤作用。AS-06 和 AS-29 可显著抑制 HEK293PS 细胞中蛋白酶体敏感荧光蛋白的降解，并诱导人多发性骨髓瘤细胞中泛素化蛋白的积累。我们表明，这些衍生物还抑制多发性骨髓瘤细胞中 NF-κB 抑制剂 IκB-α的降解和 NF-κB p65 的核转位，从而抑制 NF-κB 的激活。此外，我们证明 AS-06 和 AS-29 通过胱天蛋白酶-8 和胱天蛋白酶-9 级联诱导细胞凋亡。在异种移植小鼠模型中，静脉给予酪蛋白肽硼酸衍生物可抑制肿瘤中的蛋白酶体，并明显抑制携带人多发性骨髓瘤的小鼠的肿瘤生长。我们的研究结果表明，酪蛋白肽硼酸衍生物可能成为治疗人类多发性骨髓瘤的潜在治疗药物。
