Department of Pathology, Nantong Tumor Hospital, Nantong, Jiangsu, China.
Department of Pathology, Nantong Tumor Hospital, 30 North Tongyang Road, Pingchao, Nantong, Jiangsu, 226361, China.
Anticancer Agents Med Chem. 2019;19(5):687-696. doi: 10.2174/1871520619666190114160457.
Breast cancer is one of the leading causes of cancer deaths in female worldwide. Doxorubicin represents the most common chemotherapy for breast cancer, whereas side effects and development of resistance impede its effect on chemotherapy. Nicotinamide (NAM), serves as the sirtuins' inhibitor, effectively suppressing various types of cancer. However, the effects of NAM on drug resistance of breast cancer are need to be fully investigated.
Breast cancer doxorubicin-resistant cells MCF-7/ADR and doxorubicin-sensitive cells MCF-7 were applied in this study. Cell proliferation was assessed by CCK8 and colony-forming assays. Cell migration was evaluated by scratch test and transwell assay while cell apoptosis was measured by TUNEL analysis. Expression levels of SIRT1, phosphate Akt (P-Akt, Ser-473) and Akt were measured using western blot analysis. The interrelation between SIRT1 and Akt was investigated by co-immunoprecipitation assay.
Treatment of nicotinamide combined with doxorubicin effectively inhibited cell growth, suppressed cell migration, and promoted cell apoptosis of MCF7/ADR cells. Mechanistically, nicotinamide translocated SIRT1 from the cell nucleus to cytoplasm, dissociated the connection between SIRT1 and Akt, and consequently decreased expressions of SIRT1, and P-Akt, thereby inhibiting the growth of MCF7/ADR cells.
Our results suggested that the value of nicotinamide is a potential therapeutic agent for breast cancer treatment through downregulating SIRT1/Akt pathway, leading to the valid management of breast cancer patients.
乳腺癌是全球女性癌症死亡的主要原因之一。阿霉素是乳腺癌最常用的化疗药物，但副作用和耐药性的发展会影响其化疗效果。烟酰胺（NAM）作为 sirtuins 的抑制剂，能有效抑制多种类型的癌症。然而，NAM 对乳腺癌耐药性的影响仍需进一步研究。
本研究应用乳腺癌阿霉素耐药细胞 MCF-7/ADR 和阿霉素敏感细胞 MCF-7。用 CCK8 和集落形成实验评估细胞增殖，划痕实验和 Transwell 实验评估细胞迁移，TUNEL 分析评估细胞凋亡。用 Western blot 分析检测 SIRT1、磷酸化 Akt（P-Akt，Ser-473）和 Akt 的表达水平。用 co-immunoprecipitation assay 研究 SIRT1 和 Akt 之间的相互关系。
烟酰胺联合阿霉素治疗能有效抑制 MCF7/ADR 细胞的生长，抑制细胞迁移，促进细胞凋亡。机制上，烟酰胺将 SIRT1 从细胞核转位到细胞质，使 SIRT1 与 Akt 分离，从而降低 SIRT1 和 P-Akt 的表达，抑制 MCF7/ADR 细胞的生长。
我们的研究结果表明，烟酰胺具有下调 SIRT1/Akt 通路的潜在治疗价值，可能为乳腺癌的治疗提供新的策略。
