Sharaky Marwa, El Kiki Shereen M, Effat Heba, Mansour Heba H
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
Health Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, P.O. Box 29, Nasr City, Cairo, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 4. doi: 10.1007/s00210-025-03878-6.
The most prevalent disease in the world and the main reason for women mortality from cancer is breast cancer. The recommended treatment for hormone receptor-positive metastatic breast cancer (MBC) is cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), Abemaciclib. Radiotherapy (RT) is one of the main options to control breast cancer. This work intended to examine the impact of CDK 4/6i and palliative radiation on human breast cancer cell lines. Breast cancer cell lines (MCF7, MDA-MD-468, and MDA-MD-231) were treated with varying doses of Abemaciclib and left to incubate for 48 h. Different radiation doses were applied to the lines that had the best IC50. The intrinsic treatment objectives for MBC are presented in this study, along with the PI3K/AKT/mTOR pathway; CDK4, CDK6, and the NF-κβ/TGF-β pathway; BAX/BcL2, P53; caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9; cytokeratin 18 (CK18); cycloxygenase-2 (COX2); IL-6; IL1β; matrix metalloproteinases (MMP2 and MMP9); and oxidative stress markers. The biochemical assays revealed that abemaciclib hindered the progression of breast cancer cells MDA-MB-231 and MCF-7 and enhanced RT (10 Gy) by provoking cell cycle arrest throughout the restraint of CDK4 and CDK6 expression and increasing apoptosis, in addition to decreasing the PI3K/AKT/mTOR and NF-κβ/TGF-β pathway expression; inhibiting CK18 and COX2 activity; boosting the protein concentration of BAX and P53; and decreasing Bcl-2, IL-6, IL-1β, MMP2, and MMP9, modulating oxidative stress markers. These results implied potential effects of radiation and CDK4/6i abemaciclib on breast cancer cell lines.
世界上最常见的疾病以及女性癌症死亡的主要原因是乳腺癌。激素受体阳性转移性乳腺癌（MBC）的推荐治疗方法是细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）阿贝西利。放射治疗（RT）是控制乳腺癌的主要选择之一。这项工作旨在研究CDK 4/6i和姑息性放疗对人乳腺癌细胞系的影响。用不同剂量的阿贝西利处理乳腺癌细胞系（MCF7、MDA-MD-468和MDA-MD-231），并孵育48小时。对具有最佳半数抑制浓度（IC50）的细胞系施加不同的辐射剂量。本研究展示了MBC的内在治疗目标，以及磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号通路；细胞周期蛋白依赖性激酶4（CDK4）、细胞周期蛋白依赖性激酶6（CDK6）以及核因子κB/转化生长因子-β（NF-κβ/TGF-β）信号通路；Bcl-2相关X蛋白（BAX）/B细胞淋巴瘤-2（BcL2）、抑癌基因P53；半胱天冬酶-3、半胱天冬酶-6、半胱天冬酶-7、半胱天冬酶-8和半胱天冬酶-9；细胞角蛋白18（CK18）；环氧化酶-2（COX2）；白细胞介素-6（IL-6）；白细胞介素-1β（IL1β）；基质金属蛋白酶（MMP2和MMP9）；以及氧化应激标志物。生化分析表明，阿贝西利通过抑制CDK4和CDK6的表达引起细胞周期停滞、增加细胞凋亡，从而阻碍乳腺癌细胞MDA-MB-231和MCF-7的进展，并增强放疗（10戈瑞）效果，此外还降低PI3K/AKT/mTOR和NF-κβ/TGF-β信号通路的表达；抑制CK18和COX2的活性；提高BAX和P53的蛋白浓度；降低Bcl-2、IL-6、IL-1β、MMP2和MMP9的水平，调节氧化应激标志物。这些结果表明放疗和CDK4/6i阿贝西利对乳腺癌细胞系具有潜在影响。
