Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells.
Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells.
复制标题
DOI：
10.1111/j.1365-2141.2012.09253.x
复制
发表时间：
2012-11
影响因子：
6.5
通讯作者：
Mitsiades CS
中科院分区：
文献类型：
--
作者：
Klippel S;Jakubikova J;Delmore J;Ooi M;McMillin D;Kastritis E;Laubach J;Richardson PG;Anderson KC;Mitsiades CS
茉莉酸盐，植物应激激素，已被证明是有效的杀死各种类型的癌细胞。因此，我们在体外和体内测试了甲基茉莉酸酯（MJ）是否具有抗多发性骨髓瘤（MM）的活性。在体外实验中，MM细胞系和原代MM肿瘤细胞对MJ有反应，浓度对正常造血细胞没有显著影响，没有基质介导的耐药性。短暂暴露于MJ的MM细胞引起线粒体己糖激酶2 （HK2）的释放，ATP的快速消耗，细胞内主要信号通路的扰动，随后主要是凋亡细胞死亡。对MJ的敏感性与细胞葡萄糖消耗和乳酸生成，以及细胞内HK2蛋白水平、磷酸化电压依赖性阴离子通道2/3 （pVDAC2/3）和醛酮还原酶家族1成员C1 （AKR1C1）相关，它们代表了对MJ治疗反应性的潜在生物标志物，特别是AKR1C1转录物水平也与bortezomib或地米松治疗的MM患者的临床结果相关。有趣的是，MJ与硼替佐米体外协同作用，与载药小鼠相比，延长了MM.1S细胞弥漫性病变的免疫功能受损小鼠的存活时间（p=0.0046）。这些研究表明，茉莉酸盐代表了一种新的，有前途的策略治疗MM。
Jasmonates, plant stress hormones, have been demonstrated to be effective in killing various types of cancer cells. We therefore tested if methyljasmonate (MJ) has activity against multiple myeloma (MM) in vitro and in vivo. MM cell lines and primary MM tumour cells responded to MJ in vitro at concentrations that did not significantly affect normal haematopoietic cells, without stroma-mediated resistance. Brief MJ exposures of MM cells caused release of Hexokinase 2 (HK2) from mitochondria, rapid ATP depletion, perturbation of major intracellular signalling pathways, and ensuing mainly apoptotic cell death. Sensitivity to MJ correlated with cellular glucose consumption and lactate production, as well as intracellular protein levels of HK2, phosphorylated Voltage-dependent anion channel 2/3 (pVDAC2/3) and Aldo-keto reductase family 1 member C1 (AKR1C1), which represent potential biomarkers of responsiveness to MJ treatment, especially as AKR1C1 transcript levels also correlate with clinical outcome in bortezomib- or dexamethasone-treated MM patients. Interestingly, MJ synergized with bortezomib in vitro and prolonged survival of immunocompromised mice harbouring diffuse lesions of MM.1S cells compared to vehicle-treated mice (p=0.0046). These studies indicate that jasmonates represent a new, promising strategy to treat MM.
登录
查看更多内容
影响因子：
11.4
作者：
Ishii, Y;Kiyota, H;Honma, Y
通讯作者：
Honma, Y
影响因子：
20.3
作者：
Damiano, JS;Cress, AE;Dalton, WS
通讯作者：
Dalton, WS
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.4
作者：
Nefedova, Y;Landowski, TH;Dalton, WS
通讯作者：
Dalton, WS
影响因子：
11.2
作者：
Davies, Nicholas J.;Hayden, Rachel E.;Bunce, Chris M.
通讯作者：
Bunce, Chris M.