MK2206 enhances the cytocidal effects of bufalin in multiple myeloma by inhibiting the AKT/mTOR pathway.
MK2206 enhances the cytocidal effects of bufalin in multiple myeloma by inhibiting the AKT/mTOR pathway.
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MK2206 通过抑制 AKT/mTOR 通路增强蟾蜍灵对多发性骨髓瘤的杀细胞作用
DOI：
10.1038/cddis.2017.188
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发表时间：
2017-05-11
影响因子：
9
通讯作者：
Yan H
中科院分区：
文献类型：
--
作者：
Xiang RF;Wang Y;Zhang N;Xu WB;Cao Y;Tong J;Li JM;Wu YL;Yan H
尽管有前途的癌症治疗药物的发展，多发性骨髓瘤（MM）仍然是一种不治之症。蟾蜍灵是一种蟾蜍甾体化合物的传统中药Chan Su，以前被证明对骨髓瘤细胞系产生生长抑制作用。本课题组前期研究表明蟾蜍灵激活骨髓瘤细胞中的AKT/mTOR通路，该通路被认为是疾病进展的重要途径，并且与MM的耐药性有关。鉴于AKT在MM中的重要作用，选择变构AKT抑制剂MK 2206以增强蟾蜍灵在不同MM细胞系中的抗肿瘤作用（NCI-H929、U266、LP-1和RPMI 8226）。数据表明，MK2206通过抑制细胞增殖和诱导细胞凋亡，增强蟾毒灵在MM细胞中的细胞毒性，如通过裂解细胞凋亡相关蛋白所证明的。在外源性白细胞介素-6存在下和/或在MM细胞与骨髓基质细胞（BMSC）共培养后进一步注意到这种效果。这一过程与AKT/mTOR通路的抑制有关。蟾毒灵与MK 2206联用可降低U266细胞IL-6的分泌。联合治疗在硼替佐米耐药细胞系（NCI-H929 R，U266 R）中表现出相似的抗MM作用。除体外细胞系模型外，在原代MM细胞和BALB-c和NOD-SCID小鼠的MM异种移植物中也观察到协同效应。总之，数据表明，无论对硼替佐米的敏感性如何，MK 2206均通过抑制AKT/mTOR途径显著增强蟾蜍灵在MM细胞中的杀细胞作用。该研究为MM的有前途的治疗方法提供了基础。
Despite the development of promising cancer therapeutic drugs, multiple myeloma (MM) remains an incurable disease. Bufalin is a bufanolide steroid compound of the traditional Chinese medicine Chan Su that was previously shown to exert growth suppression effects on myeloma cell lines. Previous studies conducted by our group demonstrated that bufalin activated the AKT/mTOR pathway in myeloma cells, which is considered an essential pathway to disease progression and is related to drug resistance in MM. In view of the significant role of AKT in MM, the allosteric AKT inhibitor MK2206 was selected in order to enhance the antitumor effects of bufalin in different MM cell lines (NCI-H929, U266, LP-1 and RPMI8226). The data indicated that MK2206 enhanced the cytotoxicity of bufalin in MM cells, via the suppression of cellular proliferation and the induction of apoptosis, as demonstrated by cleavage of apoptosis-related proteins. This effect was further noted in the presence of exogenous interleukin-6 and/or following the co-culture of MM cells with bone marrow stromal cells (BMSC). This process was associated with the inhibition of the AKT/mTOR pathway. The combination of bufalin with MK2206 reduced the secretion of IL-6 in U266 cells. The combined treatment exhibited similar anti-MM effects in bortezomib-resistant cell lines (NCI-H929R, U266R). In addition to the in vitro cell line models, the synergistic effect was noted in primary MM cells and in MM xenografts of BALB-c and NOD-SCID mice. In conclusion, the data suggested that MK2206 significantly enhanced the cytocidal effects of bufalin in MM cells, regardless of the sensitivity to bortezomib, via the inhibition of the AKT/mTOR pathway. The study provided the basis of a promising treatment approach for MM.
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影响因子：
20.3
作者：
Hsu, JH;Shi, YJ;Lichtenstein, A
通讯作者：
Lichtenstein, A
影响因子：
6.2
作者：
Meng, Zhiqiang;Yang, Peiying;Shen, Yehua;Bei, Wenying;Zhang, Ying;Ge, Yongqian;Newman, Robert A.;Cohen, Lorenzo;Liu, Luming;Thornton, Bob;Chang, David Z.;Liao, Zongxing;Kurzrock, Razelle
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Kurzrock, Razelle
影响因子：
20.3
作者：
Gupta, Mamta;Ansell, Stephen M.;Witzig, Thomas E.
通讯作者：
Witzig, Thomas E.
影响因子：
3.7
作者：
Huang H;Ding Y;Sun XS;Nguyen TA
通讯作者：
Nguyen TA
影响因子：
2.7
作者：
Hashimoto, S;Jing, YK;Nakaya, K
通讯作者：
Nakaya, K