Mashinchian Milad, Vandghanooni Somayeh, Karamibonari Amir Reza, Eskandani Morteza
Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
Faculty of Veterinary Medicine, Islamic Azad University, Shabestar Branch, Shabestar, Iran.
Biochem Biophys Rep. 2025 Aug 28;44:102217. doi: 10.1016/j.bbrep.2025.102217. eCollection 2025 Dec.
Breast cancer is the most prevalent cancer among women, posing significant challenges due to its heterogeneity. Recent studies suggest that the ketogenic diet (KD) may enhance chemotherapy efficacy by modulating cancer cell metabolism, particularly through the elevation of ketone bodies like β-hydroxybutyrate (BHB). This study investigates the effects of BHB on breast cancer cells using both 2D and 3D culture models, focusing on its role in developing resistance to fluorouracil (5-FU). We utilized CF41.Mg canine mammary gland cancer cells and MCF7 human breast cancer cells to assess BHB's effects as a pre-treatment and post-treatment under varying glucose conditions. The findings indicated that BHB notably increased cell viability, proliferation, and migration. Pre-treatment resulted in a 52.94 % increase in viability for CF41.Mg cells and a 54.73 % increase for MCF7 cells after 48 h, compared to treatment with 5-FU alone. This enhancement persisted at 72 h, indicating BHB's potential to promote resistance to 5-FU. In 3D spheroid models, which better mimic the tumor microenvironment, BHB pre-treatment significantly increased spheroid size and conferred resistance to 5-FU in both cell lines. Additionally, BHB pre-treatment elevated the expression of proliferation markers such as Ki-67 and tumorigenic markers like MUC-1 (Mucin 1), while showing no significant impact on mesenchymal markers like N-cadherin and vimentin. These findings suggest that BHB significantly increases resistance to 5-FU, indicating that BHB may enable cancer cells to evade chemotherapy-induced stress. Our findings raise important questions about the potential dual role of BHB and KD in promoting cancer cell survival while potentially complicating treatment outcomes.
乳腺癌是女性中最常见的癌症，因其异质性带来了重大挑战。最近的研究表明，生酮饮食（KD）可能通过调节癌细胞代谢来提高化疗疗效，特别是通过提高β-羟基丁酸（BHB）等酮体水平。本研究使用二维和三维培养模型研究BHB对乳腺癌细胞的影响，重点关注其在对氟尿嘧啶（5-FU）产生耐药性方面的作用。我们利用CF41.Mg犬乳腺癌细胞和MCF7人乳腺癌细胞，在不同葡萄糖条件下评估BHB作为预处理和后处理的效果。研究结果表明，BHB显著提高了细胞活力、增殖和迁移能力。与单独使用5-FU治疗相比，预处理48小时后，CF41.Mg细胞的活力增加了52.94%，MCF7细胞增加了54.73%。这种增强在72小时时持续存在，表明BHB具有促进对5-FU耐药的潜力。在更好模拟肿瘤微环境的三维球体模型中，BHB预处理显著增加了球体大小，并使两种细胞系对5-FU产生耐药性。此外，BHB预处理提高了增殖标志物如Ki-67和致瘤标志物如MUC-1（粘蛋白1）的表达，而对间充质标志物如N-钙黏蛋白和波形蛋白没有显著影响。这些发现表明，BHB显著增加了对5-FU的耐药性，表明BHB可能使癌细胞逃避化疗诱导的应激。我们的发现提出了关于BHB和KD在促进癌细胞存活同时可能使治疗结果复杂化方面潜在双重作用的重要问题。
