"Química-Física Molecular", Department of Chemistry , University of Coimbra , 3004-535 Coimbra , Portugal.
Department of Life Sciences , University of Coimbra , 3000-456 Coimbra , Portugal.
J Phys Chem B. 2019 Aug 15;123(32):6968-6979. doi: 10.1021/acs.jpcb.9b05596. Epub 2019 Aug 6.
This study aimed at the development of improved drugs against human osteosarcoma, which is the most common primary bone tumor in children and teenagers with a low prognosis. New insights into the impact of an unconventional Pd(II) anticancer agent on human osteosarcoma cells were obtained by synchrotron radiation-Fourier transform infrared microspectroscopy and quasi-elastic neutron scattering (QENS) experiments from its effect on the cellular metabolism to its influence on intracellular water, which can be regarded as a potential secondary pharmacological target. Specific infrared biomarkers of drug action were identified, enabling a molecular-level description of variations in cellular biochemistry upon drug exposure. The main changes were detected in the protein and lipid cellular components, namely, in the ratio of unsaturated-to-saturated fatty acids. QENS revealed reduced water mobility within the cytoplasm for drug-treated cells, coupled to a disruption of the hydration layers of biomolecules. Additionally, the chemical and dynamical profiles of osteosarcoma cells were compared to those of metastatic breast cancer cells, revealing distinct dissimilarities that may influence drug activity.
本研究旨在开发针对人类骨肉瘤的改良药物，骨肉瘤是儿童和青少年中最常见的原发性骨肿瘤，预后较差。通过同步辐射-傅里叶变换红外微光谱和准弹性中子散射（QENS）实验，研究人员获得了一种非常规 Pd(II) 抗癌药物对人类骨肉瘤细胞影响的新见解，从其对细胞代谢的影响到对细胞内水的影响，这可以被视为一个潜在的二级药理靶点。确定了药物作用的特定红外生物标志物，能够在分子水平上描述药物暴露后细胞生物化学的变化。主要变化检测到在蛋白质和脂质细胞成分中，即不饱和脂肪酸与饱和脂肪酸的比例。QENS 显示，药物处理的细胞内细胞质的水流动性降低，同时生物分子的水合层被破坏。此外，还比较了骨肉瘤细胞和转移性乳腺癌细胞的化学和动力学特征，揭示了可能影响药物活性的明显差异。
