Mohamed Hanan R H, Michael Maivel, Elberry Yusuf, Magdy Hagar, Ismail Maryam, Eltayeb Nourhan, Safwat Gehan, Diab Ayman
Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.
Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), 6 Th of October City, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 4. doi: 10.1007/s00210-025-04323-4.
The aggressive nature and high recurrence rate of tongue cancer, along with the severe side effects associated with current conventional treatments, underscore the urgent need for alternative therapeutic strategies that offer improved selectivity and reduced toxicity. Calcium titanate nanoparticles (CaTiONPs) have previously demonstrated significant cytotoxic effects against MCF-7 breast cancer and A549 non-small cell lung cancer lines. However, their therapeutic potential against tongue cancer remains unexplored. Therefore, this study investigates, for the first time, the cytotoxic effect of CaTiONPs on HNO-97 tongue cancer cells in comparison to normal human skin fibroblasts (HSF) cells. Using various assays, we assessed their effects on cell viability, reactive oxygen species (ROS) generation, genomic DNA and mitochondrial integrity, and cell death pathways. Cytotoxicity assessment using the sulforhodamine B (SRB) assay demonstrated that CaTiONPs significantly reduced HNO-97 cell viability in a concentration-dependent manner, with an IC50 of 29.67 µg/ml. In contrast, normal HSF cells exhibited a much higher IC50 of 262.6 µg/ml, indicating strong selectivity for cancer cells (selectivity index = 8.85). Mechanistic studies revealed that HNO-97 cell exposure CaTiONPs at the IC50 concentration markedly increased ROS production, inducing oxidative stress. This led to significant genomic DNA damage, confirmed by the comet assay, and mitochondrial dysfunction, validated through Rhodamine-123 staining. Flow cytometry analysis indicated the induction of both apoptotic and necrotic pathways. At the molecular level, qRT-PCR analysis revealed significant downregulation of key genes, including the pro-apoptotic p53, the anti-apoptotic Bcl-2, and the mitochondrial ND3 gene, supporting the involvement of mitochondrial dysfunction and impaired DNA repair mechanisms in the observed cytotoxic effects. Conclusion: Collectively, these findings demonstrate that CaTiONPs elicit strong and selective multi-modal cytotoxic effects against HNO-97 tongue cancer cells and minimal impact on normal HSF cells, supporting their promise as a novel nanotherapeutic agent for tongue cancer. Further in vivo studies are needed to validate their therapeutic efficacy, clinical applicability and biosafety.
舌癌具有侵袭性且复发率高，同时当前传统治疗伴有严重的副作用，这凸显了迫切需要能提高选择性并降低毒性的替代治疗策略。钛酸钙纳米颗粒（CaTiONPs）此前已证明对MCF - 7乳腺癌细胞系和A549非小细胞肺癌细胞系具有显著的细胞毒性作用。然而，其对舌癌的治疗潜力尚未得到探索。因此，本研究首次调查了CaTiONPs对HNO - 97舌癌细胞的细胞毒性作用，并与正常人皮肤成纤维细胞（HSF）进行比较。通过各种检测方法，我们评估了它们对细胞活力、活性氧（ROS）生成、基因组DNA和线粒体完整性以及细胞死亡途径的影响。使用磺酰罗丹明B（SRB）检测进行细胞毒性评估表明，CaTiONPs以浓度依赖性方式显著降低HNO - 97细胞活力，IC50为29.67μg/ml。相比之下，正常HSF细胞的IC50高达262.6μg/ml，表明对癌细胞具有很强的选择性（选择性指数 = 8.85）。机制研究表明，以IC50浓度暴露于CaTiONPs的HNO - 97细胞显著增加了ROS产生，诱导氧化应激。这导致通过彗星试验证实的显著基因组DNA损伤以及通过罗丹明 - 123染色验证的线粒体功能障碍。流式细胞术分析表明诱导了凋亡和坏死途径。在分子水平上，qRT - PCR分析显示关键基因包括促凋亡的p53、抗凋亡的Bcl - 2和线粒体ND3基因显著下调，支持线粒体功能障碍和DNA修复机制受损参与了所观察到的细胞毒性作用。结论：总体而言，这些发现表明CaTiONPs对HNO - 97舌癌细胞具有强烈且选择性的多模式细胞毒性作用，对正常HSF细胞影响极小，支持其作为舌癌新型纳米治疗剂的前景。需要进一步的体内研究来验证其治疗效果、临床适用性和生物安全性。
