Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2019 Jan 5;842:89-98. doi: 10.1016/j.ejphar.2018.10.036. Epub 2018 Oct 27.
The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-κB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy.
磷酸肌醇 3-激酶 (PI3K) 轴与多发性骨髓瘤 (MM) 中维持肿瘤特性的关键机制之间的相关性最近已达成共识，即基于 PI3K 抑制的治疗可能为未来的治疗策略构建一个令人兴奋的前景。我们的研究结果表明，使用泛 PI3K 抑制剂 BKM120 阻断 PI3K 可通过诱导 caspase-3 依赖性凋亡并伴有 SIRT1 介导的 G2/M 期阻滞，降低 KMM-1 和 RPMI 8226 细胞系中 MM 细胞的存活率；然而，细胞对抑制剂的反应却大不相同，野生型 PTEN 表达的 RPMI 8226 细胞对抑制剂的敏感性较低。通过研究一组血液细胞系对 BKM120 的敏感性程度，我们发现与 PTEN 状态无关。据我们所知，本研究首次提出，至少部分原因是在敏感性较低的 MM 细胞中 c-Myc 或核因子 (NF)-κB 的过表达，BKM120 的抑制作用被掩盖。虽然抑制剂对 RPMI 8226 中 c-Myc 的表达没有显著影响，但我们发现当 BKM120 与 c-Myc 的小分子抑制剂联合使用时，会产生增强的细胞毒性作用。值得注意的是，协同实验的结果还表明，BKM120 与卡非佐米 (CFZ) 联合使用可产生协同抗癌作用，并提高 MM 细胞的治疗效果，这突出表明 PI3K 抑制可能是 MM 中无论是单一治疗还是联合治疗的一种合适方法。
