夹竹桃苷诱导人体细胞凋亡，但不诱导鼠细胞凋亡：Akt的去磷酸化，FasL的表达和膜流动性的改变

Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity

　

摘要

评估任何化合物作为药物的功效的常规做法是在基于细胞的体外系统中进行，然后在人体临床试验之前进行体内鼠模型。

　

夹竹桃苷,一种心脏糖苷对杀死人类细胞非常有效，但不能杀死鼠类细胞。在本报告中，我们描述了夹竹桃苷的比较分子机制，夹竹桃苷是人和小鼠细胞中的强心苷作用。用夹竹桃苷处理通过使Akt去磷酸化促进人体中FKHR的核转位，但不促进鼠细胞的核转位。它通过测定caspase激活，PARP裂解，核碎裂和膜联蛋白染色检测到，它激活人体中的MAPK和JNK，但不激活鼠细胞，并且还诱导FasL的表达导致人细胞凋亡。

　

通过HPLC评估，夹竹桃苷与人质膜相互作用，通过DPH结合检测改变其流动性，抑制Na + / K + -ATP酶活性，并且仅增加细胞内游离Ca2 +水平，然后仅在人细胞中而不是在鼠细胞中钙调神经磷酸酶活性。结果表明，人质膜可能与鼠不同，后者与夹竹桃苷相互作用，干扰Na + / K + -ATPase泵，导致钙化，随后诱导Ca2 +依赖性细胞反应如细胞凋亡。。

Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity

Abstract

Common practice to evaluate the efficacy of any compound as drug is done in cell-based in vitro system followed by in vivo murine model prior to clinical trial in human. Cardiac glycosides are very effective to kill human cells, but not murine cells. In this report, we describe the comparative molecular mechanism of oleandrin, a cardiac glycoside action in human and murine cells. Treatment with oleandrin facilitated nuclear translocation of FKHR in human, but not murine cells by dephosphorylating Akt. It activated MAPK and JNK in human, but not in murine cells and also induced expression of FasL leads to apoptosis in human cells as detected by assaying caspases activation, PARP cleavage, nuclear fragmentation, and annexin staining. Oleandrin interacted with human plasma membrane as evaluated by HPLC, altered its fluidity as detected by DPH binding, inhibited Na+/K+-ATPase activity, and increased intracellular free Ca2+ level followed by calcineurin activity only in human, but not in murine cells. Results suggest that human plasma membrane might be different than murine, which interact with oleandrin that disturb Na+/K+-ATPase pump resulting in the calcification followed by induction of Ca2+-dependent cellular responses such as apoptosis.

　

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Abbreviations

CHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonateDPHdiphenylhexatrieneFura-2AMFura-2 acetoxymethyl esterFKHRforkhead transcription factorJNKc-Jun-N-terminal kinaseMAPKmitogen activated protein kinaseNF-ATnuclear factor of activated T lymphocytesPARPpoly ADP-ribose polymerasePEphycoerythrinPIpropidium iodide

Keywords

AktFasLCalcineurinMembrane fluidityApoptosis

Molecular Immunology

Volume 44, Issue 9, March 2007, Pages 2292-2302

Molecular Immunology

Author links open overlay panelPongali B.RaghavendraYashinSreenivasanSunil K.Manna

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https://doi.org/10.1016/j.molimm.2006.11.009Get rights and content

Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity - ScienceDirect  https://www.sciencedirect.com/science/article/pii/S0161589006006791