Anti-survival and pro-apoptotic effects of meridianin C derivatives on MV4-11 human acute myeloid leukemia cells
Anti-survival and pro-apoptotic effects of meridianin C derivatives on MV4-11 human acute myeloid leukemia cells
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DOI：
10.3892/ijo.2019.4925
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发表时间：
2020-01-01
影响因子：
5.2
通讯作者：
Jang, Byeong-Churl
中科院分区：
文献类型：
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作者：
Cho, Hyorim;Yadav, Anil Kumar;Jang, Byeong-Churl
Meridianin C是一种具有抗癌活性的海洋天然产物。最近合成了几个新化合物（化合物7a-j），并报道了它们对Moloney鼠白血病病毒（PIM）激酶的前病毒整合位点的抑制作用，以及它们对人白血病细胞的抗增殖作用。然而，抗白血病的作用和作用机制的白藜芦醇C及其衍生物仍然在很大程度上未知。本研究的目的是研究野牡丹素C及其衍生物对人急性髓系白血病细胞MV 4 -11生长的影响。母体化合物野牡丹素C对MV 4 -11细胞的活力和存活没有明显影响。相比之下，MV 4 -11细胞活力和存活率被野牡丹素C衍生物降低，其中化合物7a实现了最显著的降低。化合物7a显著抑制PIM激酶的表达和活性，如通过减少B细胞淋巴瘤-2（Bcl-2）相关的死亡启动子在Ser 112处的磷酸化所证明的。然而，拟南芥素C也抑制PIM激酶的表达和活性，并且泛PIM激酶抑制剂AZD 1208仅轻微抑制MV 4 -11细胞的存活。因此，化合物7a对MV 4 -11细胞的抗存活作用与PIM激酶抑制无关。此外，化合物7a诱导细胞凋亡、半胱天冬酶-9和-3活化和聚（ADP-核糖）聚合酶（PARP）裂解，但不影响MV 4 -11细胞中死亡受体（DR）-4或DR-5的表达。化合物7a还诱导MV 4 -11细胞中裂解的Bcl-2的产生，以及髓样细胞白血病（Mcl）-1和X连锁凋亡抑制剂（XIAP）的下调。此外，化合物7a增加真核起始因子（eIF）-2 α磷酸化并降低S6磷酸化，而GRP-78表达不受影响。重要的是，在MV 4 -11细胞中，用泛半胱天冬酶抑制剂（z-VAD-favorite）处理显著减弱了化合物7a诱导的细胞凋亡、半胱天冬酶-9和半胱天冬酶-3活化、PARP切割、切割的Bcl-2的产生以及Mcl-1和XIAP的下调。总的来说，这些发现证明了化合物7a通过调节半胱天冬酶-9和-3、Bcl-2、Mcl-1、XIAP、eIF-2 α和S6分子对MV 4 -11细胞的强抗存活和促凋亡作用。
Meridianin C is a marine natural product with anticancer activity. Several meridianin C derivatives (compounds 7a-j) were recently synthesized, and their inhibitory effects on pro-viral integration site for Moloney murine leukemia virus (PIM) kinases, as well as their antiproliferative effects on human leukemia cells, were reported. However, the anti-leukemic effects and mechanisms of action of meridianin C and its derivatives remain largely unknown. The aim of the present study was to investigate the effects of meridianin C and its derivatives on MV4-11 human acute myeloid leukemia cell growth. The parent compound meridianin C did not markedly affect the viability and survival of MV4-11 cells. By contrast, MV4-11 cell viability and survival were reduced by meridianin C derivatives, with compound 7a achieving the most prominent reduction. Compound 7a notably inhibited the expression and activity of PIM kinases, as evidenced by reduced B-cell lymphoma-2 (Bcl-2)-associated death promoter phosphorylation at Ser112. However, meridianin C also suppressed PIM kinase expression and activity, and the pan-PIM kinase inhibitor AZD1208 only slightly suppressed the survival of MV4-11 cells. Thus, the anti-survival effect of compound 7a on MV4-11 cells was unrelated to PIM kinase inhibition. Moreover, compound 7a induced apoptosis, caspase-9 and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage, but did not affect death receptor (DR)-4 or DR-5 expression in MV4-11 cells. Compound 7a also induced the generation of cleaved Bcl-2, and the downregulation of myeloid cell leukemia (Mcl)-1 and X-linked inhibitor of apoptosis (XIAP) in MV4-11 cells. Furthermore, compound 7a increased eukaryotic initiation factor (eIF)-2 alpha phosphorylation and decreased S6 phosphorylation, whereas GRP-78 expression was unaffected. Importantly, treatment with a pan-caspase inhibitor (z-VAD-fmk) significantly attenuated compound 7a-induced apoptosis, caspase-9 and -3 activation, PARP cleavage, generation of cleaved Bcl-2 and downregulation of Mcl-1 and XIAP in MV4-11 cells. Collectively, these findings demonstrated the strong anti-survival and pro-apoptotic effects of compound 7a on MV4-11 cells through regulation of caspase-9 and -3, Bcl-2, Mcl-1, XIAP, eIF-2 alpha and S6 molecules.