Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu 610032, China.
Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China.
Biomed Pharmacother. 2024 Jul;176:116852. doi: 10.1016/j.biopha.2024.116852. Epub 2024 Jun 3.
The incidence of breast cancer is increasing annually, making it a major health threat for women. Chemoprevention using natural, dietary, or synthetic products has emerged as a promising approach to address this growing burden. Atractylenolide-III (AT-III), a sesquiterpenoid present in various medicinal herbs, has demonstrated potential therapeutic effects against several diseases, including tumors, nonalcoholic fatty liver disease, and cerebral ischemic injury. However, its impact on breast cancer chemoprevention remains unexplored. In this study, we used an N-methyl-N-nitrosourea (NMU)-induced rat breast cancer model and 17β-estradiol (E2)-treated MCF-10A cells to evaluate the chemopreventive potential of AT-III on mammary tumorigenesis. AT-III inhibited mammary tumor progression, evidenced by reduced tumor volume and multiplicity, prolonged tumor latency, and the reversal of NMU-induced weight loss. Furthermore, AT-III suppressed NMU-induced inflammation and oxidative stress through the Nrf2/ARE pathway in breast cancer tissues. In vitro, AT-III effectively suppressed E2-induced anchorage-independent growth and cell migration in MCF-10A cells. Nrf2 knockdown attenuated the protective effects of AT-III, highlighting the pivotal role of Nrf2 in AT-III-mediated suppression of tumorigenesis. The mechanism involves the induction of Nrf2 expression by AT-III through the autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Overall, the results of this study indicate that AT-III is a promising candidate for breast cancer chemoprevention and provide valuable insights into its molecular interactions and signaling pathways.
乳腺癌的发病率逐年上升，成为女性健康的主要威胁。使用天然、饮食或合成产品进行化学预防已成为应对这一日益增长的负担的一种有前途的方法。倍半萜内酯-III（AT-III）是一种存在于多种草药中的倍半萜烯，已被证明对多种疾病具有潜在的治疗作用，包括肿瘤、非酒精性脂肪性肝病和脑缺血性损伤。然而，其在乳腺癌化学预防中的作用仍未被探索。在这项研究中，我们使用 N-甲基-N-亚硝脲（NMU）诱导的大鼠乳腺癌模型和 17β-雌二醇（E2）处理的 MCF-10A 细胞来评估 AT-III 对乳腺肿瘤发生的化学预防潜力。AT-III 抑制了乳腺肿瘤的进展，表现为肿瘤体积和多发性减小、肿瘤潜伏期延长以及 NMU 诱导的体重减轻得到逆转。此外，AT-III 通过 Nrf2/ARE 通路抑制了乳腺癌组织中的 NMU 诱导的炎症和氧化应激。在体外，AT-III 有效抑制了 E2 诱导的 MCF-10A 细胞的无锚定依赖性生长和细胞迁移。Nrf2 敲低减弱了 AT-III 的保护作用，突出了 Nrf2 在 AT-III 介导的肿瘤抑制中的关键作用。该机制涉及 AT-III 通过自噬降解 Kelch-like ECH-associated protein 1（Keap1）诱导 Nrf2 表达。总的来说，这项研究的结果表明 AT-III 是一种有前途的乳腺癌化学预防候选物，并为其分子相互作用和信号通路提供了有价值的见解。
