Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
PLoS One. 2013 Jul 31;8(7):e70430. doi: 10.1371/journal.pone.0070430. Print 2013.
Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.
多发性骨髓瘤是一种血液系统癌症，尽管在过去十年中治疗策略有所进步，但仍被认为无法治愈。由于恶性肿瘤的异质性，针对单一途径的治疗方法不太可能成功。增殖细胞核抗原 (PCNA) 是一种多功能蛋白，对于 DNA 复制和修复至关重要，在癌细胞中常常过度表达。许多参与细胞应激反应的蛋白质通过五氨基酸序列 AlkB 同源物 2 PCNA 相互作用基序 (APIM) 与 PCNA 相互作用。因此，抑制 PCNA 的蛋白相互作用可能是同时靶向多个途径的好策略。我们最初发现，含有 APIM 序列的肽的过表达会增加癌细胞对当代治疗药物的敏感性。在这里，我们设计了一种含有穿透细胞的 APIM 的肽 ATX-101，该肽靶向 PCNA，并表明它具有抗骨髓瘤活性。我们发现，ATX-101 诱导多发性骨髓瘤细胞系和原代癌细胞凋亡，而骨髓基质细胞和原代健康淋巴细胞则不太敏感。ATX-101 诱导的细胞凋亡依赖于半胱天冬酶且与细胞周期无关。ATX-101 还增加了多发性骨髓瘤细胞对美法仑的敏感性，美法仑是一种常用于治疗多发性骨髓瘤的 DNA 损伤剂。在异种移植小鼠模型中，ATX-101 耐受性良好，并增加了美法仑的抗肿瘤活性。因此，ATX-101 通过靶向 PCNA 可能是多发性骨髓瘤治疗的一种新策略。
