Nimal Snehal, Kumbhar Navanath, Pote Manasi S, Bankar Rahul, Shaikh Mahemud, Gacche Rajesh
Department of Biotechnology, Savitribai Phule Pune University Pune, Pune, Maharashtra (MS), 411007, India.
National Centre for Cell Science, Pune, 411007, India.
Cell Commun Signal. 2025 Apr 2;23(1):163. doi: 10.1186/s12964-025-02174-3.
TNBC is an aggressive metastatic cancer that poses considerable treatment challenges because of its acquired drug resistance towards the existing targeted and hormonal therapies. The epigenetic modulation including HDACs triggers the EMT in TNBC which produces a more aggressive tumor phenotype. Chemotherapy and radiotherapy cause severe side effects which make treatment complex and challenging. To avoid these serious side effects and boost the effectiveness of current anti-cancer medications, plant flavonoids have been investigated.
The present investigation is aimed to understand the role of dietary flavonoid Gal in the modulation of epigenetic regulators such as HDACs and HATs and their impact on the reversal of the EMT process in TNBCs.
Here, we have examined the anti-TNBC potential of Gal alone and in combination with SAHA by performing series of in vitro cell culture assays such MTT, migration and invasion, cell cycle regulation, ROS generation & mitochondrial dysfunction, nuclear fragmentation & apoptosis induction etc. The expression profiles of epigenetic regulators, apoptosis regulating proteins, and EMT markers were analysed by performing transcriptomic and proteomic studies. The in vivo efficacy of Gal was studied using BALB/c mice xenograft model studies.
At IC = 50 µM/mL, Gal significantly inhibited the cell proliferation, migration, and invasion, arrested cell cycle at sub G0/G1 phases, generated ROS, reduced MMP and induced apoptosis in MDA-MB-231. Transcriptomic, proteomic, and calorimetric analysis revealed that Gal has potential to downregulate the expression of HDAC1/HDAC3 and elevate the expression levels of HAT. Gal also modulated the process of EMT by downregulating the mesenchymal markers and upregulating the epithelial marker. The synergistic mechanism of Gal and SAHA against the TNBCs was elucidated by understanding the expression levels of epigenetic regulators & EMT markers. Interestingly, Gal increased the expression of tumour suppressor protein pTEN and suppressed the expression of AKT, PI3K, and mTOR proteins involved in the cancer proliferation pathway. Gal also demonstrated impressive antitumor effect under in vivo settings.
In-vitro and In vivo studies confirmed Gal's potent anticancer efficacy and highlighted its potential as a promising therapeutic agent that possibly can be used with conventional chemotherapy against TNBC.
三阴性乳腺癌（TNBC）是一种侵袭性转移性癌症，由于其对现有靶向治疗和激素治疗产生获得性耐药，给治疗带来了相当大的挑战。包括组蛋白去乙酰化酶（HDACs）在内的表观遗传调控会引发TNBC中的上皮-间质转化（EMT），从而产生更具侵袭性的肿瘤表型。化疗和放疗会引起严重的副作用，这使得治疗变得复杂且具有挑战性。为了避免这些严重的副作用并提高当前抗癌药物的有效性，人们对植物黄酮类化合物进行了研究。
本研究旨在了解膳食黄酮类化合物Gal在调节HDACs和组蛋白乙酰转移酶（HATs）等表观遗传调节因子中的作用，以及它们对TNBC中EMT过程逆转的影响。
在这里，我们通过进行一系列体外细胞培养实验，如MTT、迁移和侵袭、细胞周期调控、活性氧（ROS）生成和线粒体功能障碍、核碎裂和凋亡诱导等，研究了Gal单独以及与伏立诺他（SAHA）联合使用时的抗TNBC潜力。通过转录组学和蛋白质组学研究分析了表观遗传调节因子、凋亡调节蛋白和EMT标志物的表达谱。使用BALB/c小鼠异种移植模型研究了Gal的体内疗效。
在IC = 50 μM/mL时，Gal显著抑制MDA-MB-231细胞的增殖、迁移和侵袭，使细胞周期停滞在亚G0/G1期，产生活性氧，降低线粒体膜电位（MMP）并诱导凋亡。转录组学、蛋白质组学和量热分析表明，Gal有下调HDAC1/HDAC3表达并提高HAT表达水平的潜力。Gal还通过下调间充质标志物并上调上皮标志物来调节EMT过程。通过了解表观遗传调节因子和EMT标志物的表达水平，阐明了Gal和SAHA联合抗TNBC的协同机制。有趣的是，Gal增加了肿瘤抑制蛋白pTEN的表达，并抑制了参与癌症增殖途径的AKT、PI3K和mTOR蛋白的表达。Gal在体内环境中也表现出显著的抗肿瘤作用。
体外和体内研究证实了Gal具有强大的抗癌功效，并突出了其作为一种有前景的治疗药物的潜力，有可能与传统化疗联合用于治疗TNBC。
