Zeng Anqi, Yu Xinyue, Chen Bao, Hao Lu, Chen Ping, Chen Xue, Tian Yuan, Zeng Jing, Hua Hua, Dai Ying, Zhao Junning
Sichuan Academy of Traditional Chinese Medicine, Chengdu, 610041, Sichuan, China.
Sichuan Institute for Translational Chinese Medicine, Chengdu, 610041, Sichuan, China.
Cancer Cell Int. 2023 Jan 27;23(1):12. doi: 10.1186/s12935-023-02850-9.
The NF-κB signaling pathway is overactivated in tumor cells, and the activation of the NF-κB signaling pathway releases a large number of inflammatory factors, which enhance tumor immunosuppression and promote tumor metastasis. The cytochrome P450 (CYP450) system consists of important metabolic enzymes present in different tissues and progressive tumors, which may lead to changes in the pharmacological action of drugs in inflammatory diseases such as tumors. In this study, the anticancer effect of tetrahydrocurcumin (THC), an active metabolite of curcumin, on breast cancer cells and the underlying mechanism were investigated. Result showed that THC selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration- and time-dependent manner. Moreover, THC-induced cell apoptosis via a mitochondria-mediated pathway, as indicated by the upregulated ratio of Bax/Bcl-2 and reactive oxygen species (ROS) induction. In addition, THC could affect the CYP450 enzyme metabolic pathway and inhibit the expression of CYP1A1 and activation of the NF-κB pathway, thereby inhibiting the migration and invasion of breast cancer cells. Furthermore, after overexpression of CYP1A1, the inhibitory effects of THC on the proliferation, metastasis, and induction of apoptosis in breast cancer cells were weakened. The knockdown of CYP1A1 significantly enhanced the inhibitory effect of THC on the proliferation, metastasis, and apoptosis induction of breast cancer cells. Notably, THC exhibited a significant tumor growth inhibition and anti-pulmonary metastasis effect in a tumor mouse model of MCF-7 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Collectively, these results showed that TH could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the CYP1A1/NF-κB signaling pathway, indicating that THC serves as a potential candidate drug for the treatment of breast cancer.
核因子κB（NF-κB）信号通路在肿瘤细胞中过度激活，NF-κB信号通路的激活释放大量炎性因子，增强肿瘤免疫抑制并促进肿瘤转移。细胞色素P450（CYP450）系统由存在于不同组织和进展期肿瘤中的重要代谢酶组成，这可能导致药物在肿瘤等炎性疾病中的药理作用发生改变。在本研究中，对姜黄素的活性代谢产物四氢姜黄素（THC）对乳腺癌细胞的抗癌作用及其潜在机制进行了研究。结果表明，THC以浓度和时间依赖性方式选择性抑制乳腺癌细胞增殖并引发凋亡。此外，THC通过线粒体介导的途径诱导细胞凋亡，Bax/Bcl-2比值上调和活性氧（ROS）诱导表明了这一点。此外，THC可影响CYP450酶代谢途径，抑制CYP1A1表达和NF-κB通路激活，从而抑制乳腺癌细胞的迁移和侵袭。此外，CYP1A1过表达后，THC对乳腺癌细胞增殖、转移和凋亡诱导的抑制作用减弱。敲低CYP1A1显著增强了THC对乳腺癌细胞增殖、转移和凋亡诱导的抑制作用。值得注意的是，THC通过调节肿瘤免疫抑制微环境，在MCF-7和4T1细胞的肿瘤小鼠模型中表现出显著的肿瘤生长抑制和抗肺转移作用。总体而言，这些结果表明，TH可通过CYP1A1/NF-κB信号通路有效触发乳腺癌细胞凋亡并抑制其迁移，表明THC是治疗乳腺癌的潜在候选药物。
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