Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
J Cell Physiol. 2019 Aug;234(8):14123-14132. doi: 10.1002/jcp.28104. Epub 2019 Jan 11.
The Wnt/β-catenin pathway is one of the most common pathways dysregulated in breast cancer, and may, therefore, be a potential-therapeutic target. We have investigated the effects of PNU-74654 in breast cancer, as a Wnt/β-catenin inhibitor, either alone or in combination with fluorouracil (5-FU). PNU-74654 suppressed cell growth at an IC of 122 ± 0.4 μmol/L and synergistically enhanced the antiproliferative activity of gemcitabine by modulating the Wnt pathway. Using a 3D cell culture model, we found that the PNU-74654 caused tumor shrinkage. It reduced the migration of MCF-7 cells (by an 18% reduction in invasive behavior) after the treatment with PNU-74654 through perturbation of E-cadherin and MMP3/9. PNU-74654/5-FU combination enhanced the percentages of cells in S-phase and significantly increased apoptosis. Moreover, our data showed that this agent was able to inhibit the growth of tumor in a xenograft model, although this effect was more pronounced in the animals treated with PNU-74654 plus 5-FU. These data show the ability of PNU-74654 to specifically target Wnt pathway, interfere with cell proliferation, induce-apoptosis, reduce-migration, and synergistically interact with 5-FU, supporting further studies on this novel therapeutic-approach for breast cancer.
Wnt/β-连环蛋白通路是乳腺癌中最常见的失调通路之一，因此可能是一个潜在的治疗靶点。我们研究了 Wnt/β-连环蛋白抑制剂 PNU-74654 单独或与氟尿嘧啶（5-FU）联合应用于乳腺癌的效果。PNU-74654 在 IC 为 122±0.4μmol/L 时抑制细胞生长，并通过调节 Wnt 通路协同增强吉西他滨的抗增殖活性。在 3D 细胞培养模型中，我们发现 PNU-74654 导致肿瘤缩小。它通过扰乱 E-钙粘蛋白和 MMP3/9，使 MCF-7 细胞的迁移减少（侵袭行为减少 18%）。PNU-74654/5-FU 联合增强了 S 期细胞的百分比，并显著增加了细胞凋亡。此外，我们的数据表明，该药物能够抑制异种移植模型中的肿瘤生长，尽管在联合使用 PNU-74654 和 5-FU 的动物中效果更为明显。这些数据表明 PNU-74654 能够特异性靶向 Wnt 通路，干扰细胞增殖，诱导细胞凋亡，减少迁移，并与 5-FU 协同相互作用，支持对这种新型乳腺癌治疗方法的进一步研究。
