Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, China.
Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, China.
J Immunol Res. 2021 Jul 22;2021:5532269. doi: 10.1155/2021/5532269. eCollection 2021.
Breast cancer is one of the most common cancers among females and is associated with high mortality and morbidity rates. Several studies have demonstrated that combination treatments with natural products and tamoxifen can improve the sensitivity and cytotoxicity of oestrogen-positive breast cancer cells in response to tamoxifen. Celastrol, a triterpene from traditional Chinese medicine, has been proven to exert significant anticancer effects on various cancers. Our study is aimed at exploring the interactive antitumour effects of celastrol combined with tamoxifen and the potential underlying anticancer mechanisms in MCF-7 cells. The results from MTT assays, isobolographic analyses, and clonogenic cell survival assays revealed that a combination of celastrol and tamoxifen exerted synergistic cytotoxic effects in MCF-7 cells. The results from Annexin V/PI staining and flow cytometry analysis suggested that celastrol enhanced tamoxifen-mediated apoptosis. In addition, exposure to a combination of celastrol and tamoxifen inhibited cell proliferation by causing G1 phase cell cycle arrest. Moreover, the distribution of LC3 was monitored by immunofluorescence, and the changes in the LC3II and P62 levels detected by western blot analysis suggested that celastrol in combination with tamoxifen triggered autophagy. Furthermore, the decrease in p-Akt and p-mTOR in MCF-7 cells, along with the increase in the autophagy marker proteins LC3II and P62, suggested that the Akt/mTOR pathway might be involved in the triggering of cell autophagy by the combination treatment. However, in an MCF-7-implanted nude mouse model, it was possible to detect significantly decreased tumour volumes and tumour weights and decreased p-Akt and p-mTOR protein expression in the celastrol+tamoxifen group. Therefore, our study provides the first evidence that celastrol combined with tamoxifen exerts synergistic anticancer effects by inducing apoptosis and autophagy in MCF-7 cells. Considering the urgent need for novel therapeutic strategies in anticancer therapy, this combinatorial approach is worthy of further investigation.
乳腺癌是女性中最常见的癌症之一，与高死亡率和发病率有关。几项研究表明，天然产物与他莫昔芬联合治疗可提高雌激素阳性乳腺癌细胞对他莫昔芬的敏感性和细胞毒性。从传统中药中提取的三萜 Celastrol 已被证明对多种癌症具有显著的抗癌作用。我们的研究旨在探索 Celastrol 与他莫昔芬联合应用的抗肿瘤相互作用及其在 MCF-7 细胞中的潜在抗癌机制。MTT 检测、等效应线分析和集落形成细胞存活检测的结果表明，Celastrol 与他莫昔芬联合应用对 MCF-7 细胞具有协同细胞毒性作用。Annexin V/PI 染色和流式细胞术分析的结果表明，Celastrol 增强了他莫昔芬介导的细胞凋亡。此外，联合应用 Celastrol 和他莫昔芬通过引起 G1 期细胞周期阻滞抑制细胞增殖。此外，通过免疫荧光监测 LC3 的分布，通过 Western blot 分析检测 LC3II 和 P62 水平的变化表明，Celastrol 与他莫昔芬联合触发自噬。此外，MCF-7 细胞中 p-Akt 和 p-mTOR 的减少以及自噬标志物蛋白 LC3II 和 P62 的增加表明，Akt/mTOR 通路可能参与了联合治疗引发的细胞自噬。然而，在 MCF-7 荷瘤裸鼠模型中，可检测到 Celastrol+他莫昔芬组肿瘤体积和重量明显减小，p-Akt 和 p-mTOR 蛋白表达降低。因此，我们的研究首次提供了证据，表明 Celastrol 与他莫昔芬联合应用通过诱导 MCF-7 细胞凋亡和自噬发挥协同抗癌作用。考虑到在癌症治疗中迫切需要新的治疗策略，这种联合方法值得进一步研究。
