Mavrogonatou Eleni, Kouroumalis Anastasios, Khaldi Lubna, Christophoridis Christophoros, Kletsas Dimitris
Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", 153 41 Athens, Greece.
Department of Pathology, "Saint Savvas" General Anticancer Oncology Hospital, 115 22 Athens, Greece.
Int J Mol Sci. 2025 Jul 30;26(15):7386. doi: 10.3390/ijms26157386.
Doxorubicin (DOX) is widely used for the treatment of several tumors, but considerable dose-dependent side effects on many normal tissues, including bones, have been reported. The aim of the present study was to follow for the first time the kinetics of DOX accumulation/clearance in the non-vascularized intervertebral disc (IVD), as well as to assess the drug's biological action in the annulus fibrosus (AF) and nucleus pulposus (NP) IVD cells and tissues. DOX was administered intravenously to rabbits before the isolation of IVDs, in which DOX quantification was performed using a highly sensitive LC-HRMS/MS analytical method. The effect of the drug on IVD cells' physiology was assessed in vitro, while IVD tissue quality post-DOX administration was studied in vivo through histological analysis. DOX delivery was found significantly lower in the IVD compared to the highly vascularized skin, declining from the outer AF to the inner NP. The low DOX concentrations reaching the IVDs had marginal effects on cells' viability, intracellular redox status, and p38 MAPK activation, while they did not evoke cellular senescence. Most importantly, the drug did not negatively affect ECM integrity, as collagen and proteoglycan content remained stable in vitro and in vivo.
阿霉素（DOX）被广泛用于多种肿瘤的治疗，但据报道，它对包括骨骼在内的许多正常组织有相当大的剂量依赖性副作用。本研究的目的是首次追踪阿霉素在无血管化椎间盘（IVD）中的蓄积/清除动力学，以及评估该药物在纤维环（AF）和髓核（NP）IVD细胞及组织中的生物学作用。在分离IVD之前，给兔子静脉注射阿霉素，然后使用高灵敏度的液相色谱-高分辨质谱/质谱分析方法对IVD中的阿霉素进行定量。在体外评估了该药物对IVD细胞生理的影响，同时通过组织学分析在体内研究了阿霉素给药后IVD组织的质量。与血管丰富的皮肤相比，发现IVD中的阿霉素递送量显著更低，从外层AF到内层NP逐渐下降。到达IVD的低阿霉素浓度对细胞活力、细胞内氧化还原状态和p38丝裂原活化蛋白激酶（MAPK）激活的影响很小，并且未引发细胞衰老。最重要的是，该药物并未对细胞外基质（ECM）完整性产生负面影响，因为胶原蛋白和蛋白聚糖含量在体外和体内均保持稳定。
