Fermented wheat germ extract inhibits glycolysis/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells
Fermented wheat germ extract inhibits glycolysis/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells
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DOI：
10.1074/jbc.m206150200
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发表时间：
2002-11-29
影响因子：
4.8
通讯作者：
Cascante, M
中科院分区：
文献类型：
--
作者：
Comín-Anduix, B;Boros, LG;Cascante, M
小麦胚芽的发酵提取物，商品名Avemar，是一种复杂的生物活性分子混合物，在各种人类恶性肿瘤中具有强大的抗转移活性。在这里，我们报道了Avemar对Jurkat白血病细胞活力、增殖、细胞周期分布、凋亡的影响，以及控制核酸合成碳流的关键糖酵解/戊糖循环酶的活性。Avemar粗粉对Jurkat肿瘤细胞的细胞毒IC50浓度为0.2 mg/ml，增加剂量抑制Jurkat细胞增殖呈剂量依赖性。浓度高于0.2 mg/ml时，Avemar对细胞生长的抑制作用超过50%（培养72 h）， 48 h时在流式直方图上出现亚g(1)峰。碘化丙啶和膜联蛋白v染色细胞的激光扫描细胞检测表明，Avemar对细胞生长的抑制作用与强烈诱导细胞凋亡一致。苯氧羰基- val - ala - asp氟甲基酮抑制细胞凋亡，但增加聚adp核糖的蛋白水解，表明半胱天冬酶介导Avemar的细胞效应。葡萄糖-6-磷酸脱氢酶和转酮醇酶活性呈剂量依赖性抑制，这与C-13掺入减少和戊糖循环底物流入RNA核糖有关。这种戊糖循环酶活性的降低和核酸前体合成碳流的减少为发酵小麦胚芽控制细胞生长和诱导细胞凋亡的作用提供了机制理解。Avemar对外周血淋巴细胞诱导生物反应的IC50 （10.02 mg/ml）约为50倍，这为这种无毒性的补充癌症治疗方式提供了广阔的治疗窗口。
The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC50 concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G(1) peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodide and annexin V-stained cells indicated that the growth-inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased C-13 incorporation and pentose cycle substrate flow into RNA ribose. This decrease in pentose cycle enzyme activities and carbon flow toward nucleic acid precursor synthesis provide the mechanistic understanding of the cell growth-controlling and apoptosis-inducing effects of fermented wheat germ. Avemar exhibits about a 50-fold higher IC50 (10.02 mg/ml) for peripheral blood lymphocytes to induce a biological response, which provides the broad therapeutic window for this supplemental cancer treatment modality with no toxic effects.