Ferjani Hanen, El Abassi Haila, Ben Salem Intidhar, Guedri Yosra, Abid Salwa, Achour Abedallatif, Bacha Hassen
a Laboratory of Research on Biologically Compatible Compounds , Faculty of Dental Medicine, University of Monastir , Monastir , Tunisia and.
b Department of Nephrology , Dialysis and Transplant, University Hospital of Sahloul , Sousse , Tunisia.
Toxicol Mech Methods. 2016;26(1):54-60. doi: 10.3109/15376516.2015.1090514. Epub 2015 Oct 13.
Tacrolimus (TAC) and Sirolimus (SRL) are produced by Streptomyces sp and effective immunosuppressive drugs commonly used in organ transplantation. Therefore, strategies for minimizing the toxicity of immunosuppressant molecules are our interest. This study was conducted to evaluate the interactive effects and the possible underlying mechanism of TAC and SRL on HCT116 cells. It was found that TAC and SRL alone inhibited cell viability. Also, it induced reactive oxygen species (ROS) formation, loss of mitochondrial membrane potential (Δψm), and able to increase DNA fragmentation in a concentration-dependent manner. The use of combined SRL and TAC showed a reservation in all toxicity observed with the two immunosuppressive drugs separately. Our result demonstrated that the mechanisms of TAC and SRL at high concentration are closely connected with oxidative stress. Furthermore, SRL at low concentration plays a protective effect against TAC (IC50) which induced cytotoxicity and genotoxicity. However, using the combination of the SRL/TAC at high concentrations (IC30) appears as an antagonist response.
他克莫司（TAC）和西罗莫司（SRL）由链霉菌属产生，是器官移植中常用的有效免疫抑制药物。因此，将免疫抑制分子毒性降至最低的策略是我们关注的焦点。本研究旨在评估TAC和SRL对HCT116细胞的相互作用及其潜在机制。研究发现，单独使用TAC和SRL会抑制细胞活力。此外，它还会诱导活性氧（ROS）生成、线粒体膜电位（Δψm）丧失，并能以浓度依赖的方式增加DNA片段化。联合使用SRL和TAC显示出对两种免疫抑制药物单独使用时所观察到的所有毒性具有缓解作用。我们的结果表明，高浓度的TAC和SRL的作用机制与氧化应激密切相关。此外，低浓度的SRL对TAC（IC50）诱导的细胞毒性和遗传毒性具有保护作用。然而，高浓度（IC30）的SRL/TAC组合似乎表现为拮抗反应。
