评估SynechocystisΔsigF突变株胞外多糖聚合物变异体的抗肿瘤潜力。
Assessing the Antitumor Potential of Variants of the Extracellular Carbohydrate Polymer from Synechocystis ΔsigF Mutant.
发表日期:2023 Mar 10
作者:
Rita Mota, Raquel T Lima, Carlos Flores, Juliana F Silva, Beatriz Cruz, Bárbara Alves, Marta T Pinto, Alessandra Adessi, Sara B Pereira, Roberto De Philippis, Paula Soares, Paula Tamagnini
来源:
Cell Death & Disease
摘要:
癌症是全球死亡率较高的疾病之一,对社会和经济的影响巨大。从天然来源中提取出的临床有效并且较为廉价的抗癌药物能够帮助克服化疗和放疗的限制和负面副作用。之前,我们发现一个Synechocystis ΔsigF过度表达突变体的胞外多糖聚合物对多种人体肿瘤细胞系具有强烈的抗肿瘤活性,通过p53和caspase-3激活诱导高水平的细胞凋亡。在这里,我们改变了ΔsigF聚合物的结构以获得变异体并在人黑色素瘤(Mewo)细胞系中进行测试。我们的结果表明,高分子量的聚合物组分对于其生物活性非常重要,而缩小肽含量则能产生具有增强的体外抗肿瘤活性的变异体。这种变异体以及原始的ΔsigF聚合物在小鸡胎盘尿囊膜(CAM)小鼠模型中进行了进一步的体内测试。两种聚合物均显著减少了移植CAM瘤的生长,对瘤形态产生了影响,从而验证了它们的体内抗肿瘤潜力。这项工作为设计和测试定制的蓝藻胞外聚合物提供了策略,并进一步加强了评估这种类型聚合物在生物技术/生物医学应用中的相关性。
Cancer is a leading cause of death worldwide with a huge societal and economic impact. Clinically effective and less expensive anticancer agents derived from natural sources can help to overcome limitations and negative side effects of chemotherapy and radiotherapy. Previously, we showed that the extracellular carbohydrate polymer of a Synechocystis ΔsigF overproducing mutant displayed a strong antitumor activity towards several human tumor cell lines, by inducing high levels of apoptosis through p53 and caspase-3 activation. Here, the ΔsigF polymer was manipulated to obtain variants that were tested in a human melanoma (Mewo) cell line. Our results demonstrated that high molecular mass fractions were important for the polymer bioactivity, and that the reduction of the peptide content generated a variant with enhanced in vitro antitumor activity. This variant, and the original ΔsigF polymer, were further tested in vivo using the chick chorioallantoic membrane (CAM) assay. Both polymers significantly decreased xenografted CAM tumor growth and affected tumor morphology, by promoting less compact tumors, validating their antitumor potential in vivo. This work contributes with strategies for the design and testing tailored cyanobacterial extracellular polymers and further strengths the relevance of evaluating this type of polymers for biotechnological/biomedical applications.