靶向微管聚合和解聚是治疗实体肿瘤的一种有前途的方法。在本研究中，我们调查了一种结构新颖的微管抑制剂[4-(4-氨基苯基)-1-(4-氟苯基)-1H-吡咯-3-基](3,4,5-三甲氧基苯基)甲酮(ARDAP)对二维和三维MCF-7乳腺癌模型中抗癌作用的分子机制。低于细胞毒性浓度下，ARDAP在MCF-7细胞中表现出明显的细胞增殖、集落形成和ATP胞内含量下降，通过细胞增殖抑制机制发挥作用。此外，药物暴露导致上皮间质转变（EMT）的阻塞。在三维细胞培养中，ARDAP对肿瘤成球的生长产生负面影响，抑制成球形成并减少ATP浓度水平。值得注意的是，ARDAP暴露促进了MCF-7细胞的分化，通过诱导：(i) Oct4和Sox2干性标记物在二维和三维模型中的表达降低，以及(ii) 在二维细胞培养中下调干细胞表面标记物CD133。有趣的是，治疗后的MCF7细胞对传统化疗药物多柔比星的细胞毒性作用表现出较高的敏感性。此外，尽管ARDAP对乳腺癌细胞具有生长抑制作用，但对健康细胞MCF10A的伤害微不足道。总之，我们的结果突出了ARDAP作为新的化疗药物或化疗治疗中的辅助化合物的潜力。 © 2023 The Authors. Archiv der Pharmazie由Wiley-VCH GmbH代表Deutsche Pharmazeutische Gesellschaft出版。

Targeting tubulin polymerization and depolymerization represents a promising approach to treat solid tumors. In this study, we investigated the molecular mechanisms underlying the anticancer effects of a structurally novel tubulin inhibitor, [4-(4-aminophenyl)-1-(4-fluorophenyl)-1H-pyrrol-3-yl](3,4,5-trimethoxyphenyl)methanone (ARDAP), in two- and three-dimensional MCF-7 breast cancer models. At sub-cytotoxic concentrations, ARDAP showed a marked decrease in cell proliferation, colony formation, and ATP intracellular content in MCF-7 cells, by acting through a cytostatic mechanism. Additionally, drug exposure caused blockage of the epithelial-to-mesenchymal transition (EMT). In 3D cell culture, ARDAP negatively affected tumor spheroid growth, with inhibition of spheroid formation and reduction of ATP concentration levels. Notably, ARDAP exposure promoted the differentiation of MCF-7 cells by inducing: (i) expression decrease of Oct4 and Sox2 stemness markers, both in 2D and 3D models, and (ii) downregulation of the stem cell surface marker CD133 in 2D cell cultures. Interestingly, treated MCF7 cells displayed a major sensitivity to cytotoxic effects of the conventional chemotherapeutic drug doxorubicin. In addition, although exhibiting growth inhibitory effects against breast cancer cells, ARDAP showed insignificant harm to MCF10A healthy cells. Collectively, our results highlight the potential of ARDAP to emerge as a new chemotherapeutic agent or adjuvant compound in chemotherapeutic treatments.© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.