Department of Breast Surgery, The First Affiliated Hospital of Sun-Yat Sen University, Guangzhou 510080, China.
Laboratory of Surgery, The First Affiliated Hospital of Sun-Yat Sen University, Guangzhou 510080, China.
Int J Mol Sci. 2023 Jun 22;24(13):10476. doi: 10.3390/ijms241310476.
Histone deacetylase inhibitor (HDACi) is a drug mainly used to treat hematological tumors and breast cancer, but its inhibitory effect on breast cancer falls short of expectations. Grape seed proanthocyanidin extract (GSPE) with abundant proanthocyanidins (PAs) has been explored for its inhibition of HDAC activity in vitro and in vivo. To enhance HDACi's effectiveness, we investigated the potential of PA to synergistically enhance HDACi chidamide (Chi), and determined the underlying mechanism. We evaluated the half-inhibitory concentration (IC50) of PA and Chi using the cell counting kit 8 (CCK8), and analyzed drugs' synergistic effect with fixed-ratio combination using the software Compusyn. Breast cancer cell's phenotypes, including short-term and long-term proliferation, migration, invasion, apoptosis, and reactive oxygen species (ROS) levels, were assessed via CCK8, clone-formation assay, wound-healing test, Transwell Matrigel invasion assay, and flow-cytometry. Protein-protein interaction analysis (PPI) and KEGG pathway analysis were used to determine the underlying mechanism of synergy. PA + Chi synergistically inhibited cell growth in T47D and MDA-MB-231 breast cancer cell lines. Short-term and long-term proliferation were significantly inhibited, while cell apoptosis was promoted. Ten signaling pathways were identified to account for the synergistic effect after RNA sequencing. Their synergism may be closely related to the steroid biosynthesis and extracellular matrix (ECM) receptor interaction pathways. PA + Chi can synergistically inhibit breast cancer cell growth and proliferation, and promote apoptosis. These effects may be related to steroid biosynthesis or the ECM receptor pathway.
组蛋白去乙酰化酶抑制剂（HDACi）主要用于治疗血液系统肿瘤和乳腺癌，但对乳腺癌的抑制作用并不理想。富含原花青素（PAs）的葡萄籽原花青素提取物（GSPE）已被探索用于其在体外和体内抑制 HDAC 活性。为了增强 HDACi 的效果，我们研究了 PA 与 HDACi 联合增强的潜力，确定了潜在的机制。我们使用细胞计数试剂盒 8（CCK8）评估了 PA 和 Chi 的半抑制浓度（IC50），并使用 CompuSyn 软件分析了药物固定比例组合的协同作用。通过 CCK8、克隆形成试验、划痕愈合试验、Transwell Matrigel 侵袭试验和流式细胞术评估乳腺癌细胞表型，包括短期和长期增殖、迁移、侵袭、凋亡和活性氧（ROS）水平。蛋白质-蛋白质相互作用分析（PPI）和 KEGG 通路分析用于确定协同作用的潜在机制。PA + Chi 协同抑制 T47D 和 MDA-MB-231 乳腺癌细胞系的细胞生长。短期和长期增殖受到显著抑制，而细胞凋亡得到促进。通过 RNA 测序鉴定了 10 个信号通路来解释协同作用。它们的协同作用可能与类固醇生物合成和细胞外基质（ECM）受体相互作用途径密切相关。PA + Chi 可以协同抑制乳腺癌细胞的生长和增殖，并促进细胞凋亡。这些作用可能与类固醇生物合成或 ECM 受体途径有关。
