真菌次生代谢产物对药物有长期的贡献,特别是在抗生素和免疫抑制剂的开发中。利用它们强大的生物活性,这些化合物现在正在探索癌症治疗,通过靶向和破坏诱导癌症进展的基因。目前的研究探讨了神经胶质毒素的抗癌潜力,真菌的次生代谢产物,其中包括整合计算预测的多方面方法,分子动力学模拟,和全面的实验验证。计算机研究已经确定了潜在的神经胶质毒素靶标,包括MAPK1,NFKB1,HIF1A,TDP1,TRIM24和CTSD参与癌症的关键通路,如NF-κB信号通路,MAPK/ERK信号通路,缺氧信号通路,Wnt/β-catenin通路,和其他基本的细胞过程。基因表达分析结果表明所有鉴定的靶标在各种乳腺癌亚型中过表达。随后的分子对接和动力学模拟揭示了胶质毒素与TDP1和HIF1A的稳定结合。对于MDA-MB-231,MDA-MB-468和MCF-7细胞,细胞活力测定显示出剂量依赖性降低模式,其显著的IC50值为0.32、0.14和0.53μM,分别。同样,在3D肿瘤球体中,神经胶质毒素的活力显着下降,表明其对实体瘤的有效性。此外,使用Real-timePCR进行的基因表达研究显示,癌症诱导基因的表达减少,MAPK1,HIF1A,胶质毒素处理后的TDP1和TRIM24。这些发现共同强调了神经胶质毒素通过多靶向促癌基因的抗癌潜力,将其定位为乳腺癌的有希望的治疗选择。
Fungal secondary metabolites have a long history of contributing to pharmaceuticals, notably in the development of antibiotics and immunosuppressants. Harnessing their potent bioactivities, these compounds are now being explored for cancer therapy, by targeting and disrupting the genes that induce cancer progression. The current study explores the anticancer potential of
gliotoxin, a fungal secondary metabolite, which encompasses a multi-faceted approach integrating computational predictions, molecular dynamics simulations, and comprehensive experimental validations. In-silico studies have identified potential
gliotoxin targets, including MAPK1, NFKB1, HIF1A, TDP1, TRIM24, and CTSD which are involved in critical pathways in cancer such as the NF-κB signaling pathway, MAPK/ERK signaling pathway, hypoxia signaling pathway, Wnt/β-catenin pathway, and other essential cellular processes. The gene expression analysis results indicated all the identified targets are overexpressed in various breast cancer subtypes. Subsequent molecular docking and dynamics simulations have revealed stable binding of
gliotoxin with TDP1 and HIF1A. Cell viability assays exhibited a dose-dependent decreasing pattern with its remarkable IC50 values of 0.32, 0.14, and 0.53 μM for MDA-MB-231, MDA-MB-468, and MCF-7 cells, respectively. Likewise, in 3D tumor spheroids, gliotoxin exhibited a notable decrease in viability indicating its effectiveness against solid tumors. Furthermore, gene expression studies using Real-time PCR revealed a reduction of expression of cancer-inducing genes, MAPK1, HIF1A, TDP1, and TRIM24 upon
gliotoxin treatment. These findings collectively underscore the promising anticancer potential of
gliotoxin through multi-targeting cancer-promoting genes, positioning it as a promising therapeutic option for breast cancer.