Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran.
Institute of Biotechnology, Shiraz University, Shiraz, Iran.
Sci Rep. 2018 Sep 17;8(1):13902. doi: 10.1038/s41598-018-32308-2.
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.
DNA 靶向抗癌药物在临床上非常成功，特别是在联合治疗中。但不幸的是，它们往往对正常细胞表现出很高的毒性。因此，人们一直在努力寻找选择性更高、毒性更低的药物。果胶是天然多糖和有益的膳食纤维，由于其抗肿瘤特性而引起了人们的关注。然而，它们的分子靶点和作用机制还知之甚少。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 MDA-MB-231、MCF-7 和 T47D 人乳腺癌细胞的活力，而对 L929 正常细胞没有毒性。在 CP 和 AP 处理后，癌细胞的 ROS 含量迅速增加，导致线粒体跨膜电位崩溃，这是 caspase 依赖性细胞凋亡的上游作用。CP 和 AP 处理的癌细胞也分别在细胞周期的 S 和 G1 或 G2/M 期停滞。此外，CP 和 AP 处理的细胞中 Galectin-3（一种涉及细胞黏附、细胞周期和细胞凋亡的多功能凝集素）的 mRNA 表达减少。CP 和 AP 对 MDA-MB-231 细胞的生长抑制与 DNA 损伤（氧化和链断裂）同时发生。在这种情况下，为了阐明作用机制，我们表明 CP 和 AP 能够与 DNA 相互作用。通过光谱技术确定了 DNA 结合的强度和模式。我们证明 CP 和 AP 通过嵌入和沟槽结合/部分嵌入分别与 dsDNA 结合。总之，我们的研究结果表明 CP 和 AP 通过增加 ROS 的释放诱导 MDA-MB-231 细胞凋亡，这可能与线粒体凋亡途径有关，并与 DNA 直接相互作用。我们的数据表明，这些化合物在癌症治疗中可能具有潜在的用途。
