Corresponding Author: Hong Chang, Toronto General Hospital, University Health Network, 200 Elizabeth Street, 11E-413, Toronto, ON M5G 2C4, Canada.
Mol Cancer Ther. 2013 Nov;12(11):2331-41. doi: 10.1158/1535-7163.MCT-12-1166. Epub 2013 Sep 12.
Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1(Met) decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells. Treatment of multiple myeloma cells with PRIMA-1(Met) resulted in induction of apoptosis, inhibition of colony formation, and migration. PRIMA-1(Met) restored wild-type conformation of mutant p53 and induced activation of p73 upregulating Noxa and downregulating Mcl-1 without significant modulation of p53 level. siRNA-mediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1(Met), whereas knockdown of p73 led to substantial attenuation of apoptotic activity in multiple myeloma cells, indicating that PRIMA-1(Met)-induced apoptosis is, at least in part, p73-dependent. Importantly, PRIMA-1(Met) delayed tumor growth and prolonged survival of mice bearing multiple myeloma tumor. Furthermore, combined treatment of PRIMA-1(Met) with dexamethasone or doxorubicin displayed synergistic effects in both multiple myeloma cell lines and primary multiple myeloma samples. Consistent with our in vitro observations, cotreatment with PRIMA-1(Met) and dexamethasone resulted in enhanced antitumor activity in vivo. Our study for the first time shows antimyeloma activity of PRIMA-1(Met) and provides the rationale for its clinical evaluation in patients with multiple myeloma, including the high-risk group with p53 mutation/deletion.
小分子 PRIMA-1(Met)/APR-246 通过靶向 p53，在多种癌症类型中显示出有前景的临床前活性。然而，PRIMA-1(Met)诱导细胞凋亡的机制尚不完全清楚，其对多发性骨髓瘤细胞的影响也尚不清楚。在这项研究中，我们评估了 PRIMA-1(Met)单独或与当前抗骨髓瘤药物联合治疗多发性骨髓瘤细胞系、患者样本和小鼠异种移植模型的抗肿瘤效果。我们的研究结果表明，PRIMA-1(Met)降低了多发性骨髓瘤细胞的活力，无论 p53 状态如何，对正常造血细胞的细胞毒性有限。用 PRIMA-1(Met)处理多发性骨髓瘤细胞导致细胞凋亡、集落形成和迁移抑制。PRIMA-1(Met)恢复了突变 p53 的野生型构象，并诱导 p73 的激活，上调 Noxa，下调 Mcl-1，而对 p53 水平没有显著调节。p53 的 siRNA 介导的沉默对 PRIMA-1(Met)诱导的细胞凋亡反应影响不大，而 p73 的敲低导致多发性骨髓瘤细胞的凋亡活性显著减弱，表明 PRIMA-1(Met)诱导的细胞凋亡至少部分依赖于 p73。重要的是，PRIMA-1(Met)延迟了多发性骨髓瘤肿瘤小鼠的肿瘤生长并延长了其生存时间。此外，PRIMA-1(Met)与地塞米松或多柔比星联合治疗在多发性骨髓瘤细胞系和原发性多发性骨髓瘤样本中均显示出协同作用。与我们的体外观察结果一致，PRIMA-1(Met)和地塞米松联合治疗在体内增强了抗肿瘤活性。我们的研究首次表明 PRIMA-1(Met)具有抗骨髓瘤活性，并为其在多发性骨髓瘤患者中的临床评估提供了依据，包括具有 p53 突变/缺失的高危患者。
