Inhibition of autophagy augments the anticancer activity of α-mangostin in chronic myeloid leukemia cells
Inhibition of autophagy augments the anticancer activity of α-mangostin in chronic myeloid leukemia cells
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DOI：
10.3109/10428194.2013.802312
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发表时间：
2014-03-01
影响因子：
2.6
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
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作者：
Chen, Jia-Jie;Long, Zi-Jie;Liu, Quentin
具有抗癌活性的天然产物因其低毒和潜在的作用而被广泛研究。α-芒果苷是山竹中的一种成分，是一种具有抗氧化和抗肿瘤特性的口山酮衍生物。本研究旨在探讨如何提高α-芒果苷对携带野生型bcr-abl或bcr-abl-T315I突变的慢性髓系白血病(CML)细胞的抗癌作用。我们发现α-芒果苷对K562、KBM5和KBM5-T315I细胞的增殖均有抑制作用，且呈时间和剂量依赖关系。显著地，与对照细胞相比，α-芒果苷增加了凋亡细胞的数量，并诱导了DNA片段化。此外，α-芒果苷选择性地抑制原代CML细胞的增殖，而在正常造血祖细胞中显示出有限的致死性。此外，α-芒果苷不仅能诱导CML细胞的凋亡，还能诱导细胞自噬。Alpha-Mangostin显著增加哺乳动物自噬标记LC-3II的表达水平，并增加自噬空泡(AVs)的积累。氯喹抑制自噬通过增加细胞凋亡来增强α-芒果苷介导的细胞毒作用。综上所述，我们的数据表明，以自噬通路为靶点是一种有希望的治疗策略，可以增强α-芒果苷诱导的细胞凋亡。我们的研究为今后的研究提供了一种方法，以探索这种联合治疗CML的方法。
Natural products possessing anticancer activity have been extensively studied because of their low toxicity and potential effect. alpha-Mangostin, a component of Garcinia mangostana Linn, is a xanthone derivative shown to have antioxidant and antitumor properties. This study was carried out to investigate how to improve the anticancer effects of alpha-mangostin in chronic myeloid leukemia (CML) cell lines bearing wild-type BCR-ABL or BCR-ABL-T315Imutation. We showed that alpha-mangostin inhibited cell proliferation of K562, KBM5 and KBM5-T315I cells in both a time- and dose-dependent manner. Significantly, alpha-mangostin increased the number of apoptotic cells and induced DNA fragmentation compared to control cells. Moreover, alpha-mangostin selectively inhibited proliferation in primary CML cells, while showing limited lethality in normal hematopoietic progenitors. Additionally, alpha-mangostin induced not only apoptosis but also autophagy in CML cells. alpha-Mangostin dramatically increased the expression levels of LC-3II, an autophagosome marker in mammals, and the accumulation of autophagic vacuoles (AVs). Inhibition of autophagy by chloroquine enhanced alpha-mangostin-mediated cytotoxicity through increasing apoptosis. Taken together, our data suggest that targeting the autophagy pathway is a promising therapeutic strategy to enhance alpha-mangostin-induced apoptosis. Our study provides an approach for future studies to explore this combination for the treatment of CML.