Molecular Physical-Chemistry R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, UK.
Spectrochim Acta A Mol Biomol Spectrosc. 2024 Sep 5;317:124389. doi: 10.1016/j.saa.2024.124389. Epub 2024 May 1.
Over the years, osteosarcoma therapy has had a significative improvement with the use of a multidrug regime strategy, increasing the survival rates from less than 20 % to circa 70 %. Different types of development of new antineoplastic agents are critical to achieve irreversible damage to cancer cells, while preserving the integrity of their healthy counterparts. In the present study, complexes with two and three Pd(II) centres linked by the biogenic polyamines: spermine (PdSpmCl) and spermidine (PdSpdCl) were tested against non-malignant (osteoblasts, HOb) and cancer (osteosarcoma, MG-63) human cell lines. Either alone or in combination according to the EURAMOS-1 protocol, they were used versus cisplatin as a drug reference. By evaluating the cytotoxic effects of both therapeutic approaches (single and drug combination) in HOb and MG-63 cell lines, the selective anti-tumoral potential is assessed. To understand the different treatments at a molecular level, Synchrotron Radiation Fourier Transform Infrared and Raman microspectroscopies were applied. Principal component analysis and hierarchical cluster analysis are applied to the vibrational data, revealing the major metabolic changes caused by each drug, which were found to rely on DNA, lipids, and proteins, acting as biomarkers of drug-to-cell impact. The main changes were observed for the B-DNA native conformation to either Z-DNA (higher in the presence of polynuclear complexes) or A-DNA (preferably after cisplatin exposure). Additionally, a higher effect upon variation in proteins content was detected in drug combination when compared to single drug administration proving the efficacy of the EURAMOS-1 protocol with the new drugs tested.
多年来，通过使用多药物治疗方案策略，骨肉瘤治疗取得了显著进展，将生存率从低于 20%提高到了大约 70%。开发新型抗肿瘤药物的不同类型对于实现对癌细胞的不可逆损伤，同时保持其健康对应物的完整性至关重要。在本研究中，测试了两种和三种通过生物多胺（精胺（PdSpmCl）和亚精胺（PdSpdCl））连接的 Pd(II)中心的配合物针对非恶性（成骨细胞，HOb）和癌症（骨肉瘤，MG-63）人细胞系。根据 EURAMOS-1 方案，它们单独或与顺铂联合使用作为药物参考。通过评估两种治疗方法（单一治疗和药物联合治疗）在 HOb 和 MG-63 细胞系中的细胞毒性作用，评估其选择性抗肿瘤潜力。为了在分子水平上理解不同的治疗方法，应用同步辐射傅里叶变换红外和拉曼显微镜。主成分分析和层次聚类分析应用于振动数据，揭示了每种药物引起的主要代谢变化，这些变化依赖于 DNA、脂质和蛋白质，作为药物对细胞影响的生物标志物。主要变化观察到 B-DNA 天然构象向 Z-DNA（在多核配合物存在时更高）或 A-DNA（在顺铂暴露后更好）的转变。此外，与单一药物给药相比，药物联合治疗时检测到蛋白质含量的变化更大，证明了新药物测试的 EURAMOS-1 方案的有效性。
