Machado Raiane Aparecida Dos Santos, Siqueira Raoni Pais, da Silva Fernanda Cardoso, Matos André Carlos Pereira de, Borges Dayanne Silva, Rocha Gislaine Gonçalves, Souza Thais Cristina Prado de, Souza Rafael Aparecido Carvalho, Oliveira Clayton Rodrigues de, Ferreira Antônio G, Maia Pedro Ivo da Silva, Deflon Victor Marcelo, Oliveira Carolina Gonçalves, Araújo Thaise Gonçalves
Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas 38700-002, MG, Brazil.
Institute of Chemistry, Federal University of Uberlândia, Uberlândia 38400-902, MG, Brazil.
Pharmaceutics. 2024 Dec 18;16(12):1610. doi: 10.3390/pharmaceutics16121610.
: Triple-negative breast cancer (TNBC) is the most challenging molecular subtype of breast cancer (BC) in clinical practice, associated with a worse prognosis due to limited treatment strategies and its insensitivity to conventional drugs. Zinc is an important trace element for homeostasis, and its Schiff base metal complexes have shown promise in treating advanced tumors. In this study, four new heteroleptic Zn(II) complexes (-) with Schiff bases were synthesized, characterized, and evaluated for their activity in BC cells. : Compounds were synthesized, characterized, and their crystal structures were determined. Biological activity was assessed using MTT, clonogenic, scratch wound healing, caspase 3 and 8 activity, qPCR, and chemosensitization assays. : The complexes exhibited cytotoxicity against MCF-7 (luminal BC), MDA-MB-453 (HER2-positive BC), and MDA-MB-231 (TNBC) cell lines, with IC values ranging from 0.01 to 20 µM. Complex showed reduced cytotoxicity toward non-tumor cell lines. This, complexation with Zn(II) increased the cytotoxicity of the ligands, a trend not observed for complexes -. Due to its favorable profile, complex was selected for further assays, in which it inhibited colony formation and the cell migration of TNBC cells in a dose-dependent manner. Furthermore, this compound induced cell death independently of caspases, decreasing the activity of caspase 8. Interestingly, complex sensitized TBNC cells to doxorubicin and paclitaxel, possibly modulating the epithelial-mesenchymal transition mechanism, as evidenced by increased expression. : Results suggest the potential of complex in sensitizing aggressive BC cells to chemotherapy, proving to be a promising alternative in cases of therapeutic failure.
三阴性乳腺癌（TNBC）是临床实践中最具挑战性的乳腺癌（BC）分子亚型，由于治疗策略有限且对传统药物不敏感，其预后较差。锌是维持体内平衡的重要微量元素，其席夫碱金属配合物在治疗晚期肿瘤方面已显示出前景。在本研究中，合成、表征了四种新的含席夫碱的异配体Zn（II）配合物（-），并评估了它们在BC细胞中的活性。：合成并表征了化合物，测定了它们的晶体结构。使用MTT、克隆形成、划痕伤口愈合、半胱天冬酶3和8活性、qPCR和化学增敏试验评估生物活性。：这些配合物对MCF-7（管腔型BC）、MDA-MB-453（HER2阳性BC）和MDA-MB-231（TNBC）细胞系表现出细胞毒性，IC值范围为0.01至20μM。配合物对非肿瘤细胞系的细胞毒性降低。因此，与Zn（II）络合增加了配体的细胞毒性，这一趋势在配合物-中未观察到。由于其良好的特性，选择配合物进行进一步试验，其中它以剂量依赖性方式抑制TNBC细胞的集落形成和细胞迁移。此外，该化合物独立于半胱天冬酶诱导细胞死亡，降低半胱天冬酶8的活性。有趣的是，配合物使TBNC细胞对多柔比星和紫杉醇敏感，可能调节上皮-间质转化机制，如表达增加所证明。：结果表明配合物在使侵袭性BC细胞对化疗敏感方面具有潜力，在治疗失败的情况下被证明是一种有前途的替代方法。
