UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Bioorg Med Chem. 2021 Jan 15;30:115880. doi: 10.1016/j.bmc.2020.115880. Epub 2020 Dec 15.
Cancer is still one of the deadliest diseases worldwide despite the efforts in its early detection and treatment strategies. However, most chemotherapeutic agents still present side effects in normal tissues and acquired resistance that limit their efficacy. Spiropyrazoline oxindoles might be good alternatives as they have shown antiproliferative activity in human breast and colon cancer cell lines, without eliciting cytotoxicity in healthy cells. However, their potential for ovarian cancer was never tested. In this work, the antiproliferative activity of five spiropyrazoline oxindoles was assessed in ovarian cancer cells A2780 and the biological targets and mechanism of action of the most promising compound evaluated. Compound 1a showed the highest antiproliferative effect, as well as the highest selectivity for A2780 cells compared to healthy fibroblasts. This antiproliferative effect results from the induction of cell death by mitochondria-mediated apoptosis and autophagy. In vitro DNA interaction studies demonstrated that 1a interacts with DNA by groove-binding, without triggering genotoxicity. In addition, 1a showed a strong affinity to bovine serum albumin that might be important for further inclusion in drug delivery platforms. Proteomic studies reinforced 1a role in promoting A2780 endoplasmatic reticulum (ER) stress by destabilizing the correct protein folding which triggers cell death via apoptosis and autophagy.
尽管在癌症的早期检测和治疗策略方面已经做出了努力，但癌症仍然是全球范围内最致命的疾病之一。然而，大多数化疗药物在正常组织中仍存在副作用，并产生获得性耐药性，从而限制了它们的疗效。螺吡喃并吲哚酮类化合物可能是一种较好的替代品，因为它们在人乳腺癌和结肠癌细胞系中表现出抗增殖活性，而对健康细胞没有细胞毒性。然而，它们对卵巢癌的潜在作用从未被测试过。在这项工作中，评估了五种螺吡喃并吲哚酮类化合物对卵巢癌细胞 A2780 的抗增殖活性，并评估了最有前途的化合物的生物靶标和作用机制。化合物 1a 表现出最高的抗增殖活性，并且与健康成纤维细胞相比，对 A2780 细胞具有最高的选择性。这种抗增殖作用是通过线粒体介导的细胞凋亡和自噬诱导细胞死亡产生的。体外 DNA 相互作用研究表明，1a 通过沟结合与 DNA 相互作用，而不会引发遗传毒性。此外，1a 与牛血清白蛋白具有很强的亲和力，这对于进一步纳入药物输送平台可能很重要。蛋白质组学研究证实了 1a 通过破坏正确的蛋白质折叠来促进 A2780 内质网（ER）应激的作用，这通过细胞凋亡和自噬引发细胞死亡。
