Experimental Pathology Laboratory, Federal University of São João del Rei (UFSJ), Rua Sebastião Gonçalves Coelho, 400, Chanadour, Divinópolis, 35501-296, MG, Brazil.
Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais (UFMG), Avenida Antônio Carlos, 6627, Pampulha, Belo Horizonte, 31270-901, MG, Brazil.
Asian Pac J Cancer Prev. 2024 Nov 1;25(11):3935-3946. doi: 10.31557/APJCP.2024.25.11.3935.
Breast cancer represents the most prevalent type of tumor throughout the world. Considering the side effects caused by the available treatments, the resistance acquired by cells to cytotoxic agents, and metastasis, it is necessary to search for new sources of antitumor and antimetastatic therapies. Given the numerous antitumor studies involving the synthesis of substances derived from the naphthoquinone lapachol, we investigated the antineoplastic potential of a new synthetic substance (APO-3) derived from lapachol, alone and in combination with the chemotherapeutic agent paclitaxel (PTX), against 4T1 cells, a murine breast cancer cell line.
METHODS/RESULTS: In MTT assay APO-3 and the APO-3/PTX combination were selectively cytotoxic to 4T1 cells, with APO-3/PTX being approximately 6.5 and 15 times more selective than PTX and APO-3, respectively. After zymography, APO-3/PTX was more effective in decreasing matrix metalloproteinase-9 (MMP-9) activity compared with APO-3 alone. In the clonogenic assay, APO-3/PTX reduced the number of colonies more effectively than APO-3 or PTX alone. APO-3/PTX also inhibited cell migration, as did PTX and APO-3 alone. The combination increased the expression of proteins involved in the intrinsic apoptotic pathway and induced cellular morphological changes characteristic of this type of cell death, acting similarly to PTX alone. APO-3 increased Receptor-interacting serine/threonine-protein kinase 1 (RIP1) and caused morphological changes characteristic of apoptosis and necroptosis in 4T1 cells.
Taken together, APO-3 presented antitumor action against 4T1 cells, but the APO-3/PTX combination was more effective than either substance alone.
乳腺癌是全球最常见的肿瘤类型。考虑到现有治疗方法引起的副作用、细胞对细胞毒剂的耐药性以及转移，有必要寻找新的抗肿瘤和抗转移治疗方法。鉴于涉及来源于萘醌拉帕醌的物质合成的众多抗肿瘤研究，我们研究了一种新的合成物质（APO-3）单独和与化疗药物紫杉醇（PTX）联合对 4T1 细胞（一种鼠乳腺癌细胞系）的抗肿瘤潜力。
方法/结果：在 MTT 测定中，APO-3 和 APO-3/PTX 组合对 4T1 细胞具有选择性细胞毒性，APO-3/PTX 分别比 PTX 和 APO-3 约高 6.5 和 15 倍。在明胶酶谱分析后，APO-3/PTX 比单独的 APO-3 更有效地降低基质金属蛋白酶-9（MMP-9）活性。在集落形成试验中，APO-3/PTX 比 APO-3 或 PTX 单独更有效地减少菌落数量。APO-3/PTX 还抑制细胞迁移，PTX 和 APO-3 单独也有抑制作用。该组合增加了参与内在凋亡途径的蛋白质的表达，并诱导了细胞形态变化，这与单独使用 PTX 相似。APO-3 增加了受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIP1）的表达，并导致 4T1 细胞出现凋亡和坏死样细胞死亡的形态变化。
综上所述，APO-3 对 4T1 细胞具有抗肿瘤作用，但 APO-3/PTX 联合用药比单独使用任何一种药物都更有效。
