Oxidative DNA damage induced by ROS-modulating agents with the ability to target DNA: A comparison of the biological characteristics of citrus pectin and apple pectin.
Oxidative DNA damage induced by ROS-modulating agents with the ability to target DNA: A comparison of the biological characteristics of citrus pectin and apple pectin.
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DOI：
10.1038/s41598-018-32308-2
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发表时间：
2018-09-17
影响因子：
4.6
通讯作者：
Ardestani SK
中科院分区：
文献类型：
--
作者：
Salehi F;Behboudi H;Kavoosi G;Ardestani SK
DNA靶向抗癌药物已经在临床上取得了很大的成功，特别是在联合治疗方面。但不幸的是，它们往往对正常细胞表现出高水平的毒性。因此，人们一直在努力寻找具有更高选择性和更低毒性的试剂。果胶是一种天然多糖，是一种有益的营养纤维，因其抗肿瘤特性而备受关注。然而，它们的分子靶点和作用机制却鲜为人知。在这里，我们报道了柑橘果胶(CP)和苹果果胶(AP)选择性地抑制人乳腺癌细胞MDA-MB-231、MCF-7和T47D的活力，而对L929正常细胞无毒。在CP和AP处理后，癌细胞的ROS含量迅速增加，并导致线粒体跨膜电位崩溃，线粒体跨膜电位作用于caspase依赖的细胞凋亡的上游。CP和AP处理的癌细胞也分别被阻滞在细胞周期的G1期和G2/M期。此外，在CP和AP处理的细胞中，Galectin-3(一种参与细胞黏附、细胞周期和凋亡的多功能凝集素)的mRNA表达都减少了。CP抑制MDA-MB-231细胞生长，AP伴随DNA损伤(氧化和链断裂)。在此背景下，为了阐明作用机制，我们证明了CP和AP能够与DNA相互作用。用光谱技术确定了DNA的结合强度和结合方式。我们证明了CP和AP分别以插层和沟槽结合/部分插层的方式与dsDNA结合。综上所述，我们的研究结果表明，CP和AP可能通过增加ROS的释放而诱导MDA-MB-231细胞的凋亡，这可能与线粒体的凋亡途径有关，并直接与DNA相互作用。我们的数据表明，这些化合物可能在癌症治疗中有潜在的用处。
DNA targeting anticancer agents have been very successful in clinic, especially, when used in combinatorial therapy. But unfortunately, they often exhibit high levels of toxicity towards normal cells. Hence, much effort has been put into finding agents with more selectivity, and less toxicity. Pectins are natural polysaccharides, and beneficial nutritional fibers that have attracted attentions due to their antitumor properties. However, their molecular targets, and mechanism of action are widely unknown. Here, we have reported that citrus pectin (CP) and apple pectin (AP) selectively suppress viability in MDA-MB-231, MCF-7 and T47D human Breast cancer cells, while non-toxic to L929 normal cells. Upon CP, and AP treatments, cancer cells’ ROS content increased rapidly, and led to the collapse of the mitochondrial transmembrane potential which functions upstream of the caspase-dependent apoptosis. CP and AP treated cancer cells were also arrested at the S and G1 or G2/M phases of the cell cycle, respectively. Furthermore, mRNA expression of Galectin-3 (a multi-functional lectin involved in cell adhesion, cell cycle, and apoptosis) reduced in both CP and AP treated cells. Growth inhibition of MDA-MB-231 cells by CP, and AP was concomitant with DNA damage (oxidation, and strand breaks). In this context, in an effort to clarify the mechanism of action, we showed that CP, and AP are able to interact with DNA. The strength and mode of DNA binding were established by spectroscopy techniques. We demonstrated that CP, and AP bind to dsDNA by intercalation, and groove binding/partial intercalation, respectively. In conclusion, our findings suggest that CP, and AP induce apoptosis in MDA-MB-231 cells by increasing the release of ROS, which may be related to the mitochondrial apoptosis pathway, and direct interactions with DNA. Our data indicate that these compounds may be potentially useful in cancer treatment.
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DNA不匹配修复和氧化DNA损伤：对癌症生物学和治疗的影响。
影响因子：
5.2
作者：
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通讯作者：
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影响因子：
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作者：
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