Mussa Ali, Hamid Mahasin, Hajissa Khalid, Murtadha Ahmad Hafiz, Al-Hatamleh Mohammad A I, Mokhtar Noor Fatmawati, Uskoković Vuk, Plebanski Magdalena, Mohamud Rohimah, Hassan Rosline
Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia.
Department of Biology, Faculty of Education, Omdurman Islamic University, P.O. Box 382, Omdurman, Sudan.
J Transl Med. 2025 Jan 8;23(1):31. doi: 10.1186/s12967-024-06016-7.
Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and its potential benefits remain under debate. Herein, we investigate the activity and mechanism of action of pharmacological Vit-C on two BC tumor spheroids.
We developed two distinct types of BC tumor spheroids from MDA-MB-231 and MCF-7 cells. The spheroids underwent treatment with a range of concentrations of pharmacological Vit-C (1, 5, 10, 15, and 20 mM). Assessments were conducted to determine the cell viability, HO levels, glutathione-to-glutathione disulfide (GSH/GSSG) ratios, and apoptosis. Both flow cytometry analyses of Annexin V/PI staining and caspase3/7 activity assay were used to check apoptosis.
We showed that Vit-C induced dose-dependent cell death in both types of tumor spheroids, primarily driven by elevated HO production and a concomitant oxidative stress imbalance induced by the GSH depletion. The high levels of HO generated by Vit-C triggered the apoptosis of spheroids. In MCF-7 spheroids, Vit-C-induced HO production was higher, with a more pronounced decrease in the GSH/GSSG ratio, indicating greater susceptibility to oxidative stress-induced cell death. However, MDA-MB-231 spheroids exhibited a more severe cytotoxic response.
This study reveals that Vit-C induces oxidative stress-mediated cell death in both non-aggressive and aggressive BC spheroids. Unlike traditional in vitro studies, this work provides novel insights into the response of two BC tumor subtypes to Vit-C, demonstrating its potential as a targeted common therapy for BC.
药理维生素C（Vit-C）或高剂量Vit-C最近作为一种潜在的癌症治疗方法受到关注。然而，Vit-C的抗癌活性尚未在真实的人类癌症三维模型中进行研究，尤其是关于乳腺癌（BC），其潜在益处仍存在争议。在此，我们研究了药理Vit-C对两种BC肿瘤球体的活性和作用机制。
我们从MDA-MB-231和MCF-7细胞中培养出两种不同类型的BC肿瘤球体。这些球体用一系列浓度的药理Vit-C（1、5、10、15和20 mM）进行处理。进行评估以确定细胞活力、HO水平、谷胱甘肽与谷胱甘肽二硫化物（GSH/GSSG）比值以及细胞凋亡情况。使用Annexin V/PI染色的流式细胞术分析和caspase3/7活性测定来检查细胞凋亡。
我们表明，Vit-C在两种类型的肿瘤球体中均诱导剂量依赖性细胞死亡，主要由HO产生增加以及GSH消耗诱导的氧化应激失衡所驱动。Vit-C产生的高水平HO引发了球体的凋亡。在MCF-7球体中，Vit-C诱导的HO产生更高，GSH/GSSG比值下降更明显，表明对氧化应激诱导的细胞死亡更敏感。然而，MDA-MB-231球体表现出更严重的细胞毒性反应。
本研究表明，Vit-C在非侵袭性和侵袭性BC球体中均诱导氧化应激介导的细胞死亡。与传统的体外研究不同，这项工作为两种BC肿瘤亚型对Vit-C的反应提供了新的见解，证明了其作为BC靶向通用疗法的潜力。
