Phamacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
PLoS One. 2012;7(9):e44093. doi: 10.1371/journal.pone.0044093. Epub 2012 Sep 6.
α-Tomatine, a tomato glycoalkaloid, has been reported to possess antibiotic properties against human pathogens. However, the mechanism of its action against leukemia remains unclear. In this study, the therapeutic potential of α-tomatine against leukemic cells was evaluated in vitro and in vivo. Cell viability experiments showed that α-tomatine had significant cytotoxic effects on the human leukemia cancer cell lines HL60 and K562, and the cells were found to be in the Annexin V-positive/propidium iodide-negative phase of cell death. In addition, α-tomatine induced both HL60 and K562 cell apoptosis in a cell cycle- and caspase-independent manner. α-Tomatine exposure led to a loss of the mitochrondrial membrane potential, and this finding was consistent with that observed on activation of the Bak and Mcl-1 short form (Mcl-1s) proteins. Exposure to α-tomatine also triggered the release of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus and down-regulated survivin expression. Furthermore, α-tomatine significantly inhibited HL60 xenograft tumor growth without causing loss of body weight in severe combined immunodeficiency (SCID) mice. Immunohistochemical test showed that the reduced tumor growth in the α-tomatine-treated mice was a result of increased apoptosis, which was associated with increased translocation of AIF in the nucleus and decreased survivin expression ex vivo. These results suggest that α-tomatine may be a candidate for leukemia treatment.
α-茄碱是一种番茄糖苷生物碱，据报道具有抗人类病原体的抗生素特性。然而，其对抗白血病的作用机制尚不清楚。在这项研究中，评估了α-茄碱在体外和体内对白血病细胞的治疗潜力。细胞活力实验表明，α-茄碱对人白血病癌细胞系 HL60 和 K562 具有显著的细胞毒性作用，并且这些细胞处于细胞死亡的 Annexin V 阳性/碘化丙啶阴性阶段。此外，α-茄碱以细胞周期和 caspase 独立的方式诱导 HL60 和 K562 细胞凋亡。α-茄碱暴露导致线粒体膜电位丧失，这一发现与 Bak 和 Mcl-1 短型（Mcl-1s）蛋白激活时观察到的结果一致。α-茄碱的暴露还触发了凋亡诱导因子（AIF）从线粒体释放到细胞核，并下调了 survivin 的表达。此外，α-茄碱在严重联合免疫缺陷（SCID）小鼠中显著抑制 HL60 异种移植肿瘤生长，而不会导致体重减轻。免疫组织化学测试表明，α-茄碱处理的小鼠中肿瘤生长减少是由于细胞凋亡增加所致，这与细胞核中 AIF 的易位增加和 survivin 表达的减少有关。这些结果表明，α-茄碱可能是白血病治疗的候选药物。
