Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy.
Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.
J Cell Biochem. 2018 Jun;119(6):4845-4854. doi: 10.1002/jcb.26686. Epub 2018 Mar 1.
In clinical practice for the treatment of chronic myeloid leukemia, second generation of tyrosine kinase inhibitors such as Nilotinib (NIL) specific and potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS) a inhibitor of BCR/ABL and Src family kinase were developed to clinically overcome imatinib resistance. In this study, we wanted to test the ability of some antioxidants such Resveratrol (RES) or a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) or δ-tocotrienol (δ-TOCO) to interact with DAS and NIL on viability, reactive oxygen species (ROS) production, lipid peroxidation, and apoptosis. To test the possible mechanisms of action of such antioxidants, we utilized N-acetyl-L-cysteine (NAC) a specific inhibitor ROS production or PP1 a specific Src tyrosine kinase inhibitor or BAPTA a specific chelator of intracellular calcium. Our data demonstrated: 1) RES, rMnSOD, δ-TOCO, and NAC, at dose used, significantly reduced the intracellular levels of MDA induced by DAS or NIL; 2) RES, rMnSOD, and δ-TOCO increased the intracellular ROS levels; 3) The increase ROS levels is related to higher levels of oligonucleosomesi induced by DAS and NIL and that NAC significantly reduced this activity. Interestingly, our data showed that apoptotic activity of DAS and NIL have significantly increased the production of oligonucleosomes by triggering excessive ROS generation as well as functionality of SERCA receptors.
在慢性髓性白血病的临床治疗中，开发了第二代酪氨酸激酶抑制剂，如尼罗替尼（NIL），它是 BCR/ABL 激酶的特异性和强效抑制剂，达沙替尼（DAS）是 BCR/ABL 和 Src 家族激酶的抑制剂，以临床克服伊马替尼耐药性。在这项研究中，我们想测试一些抗氧化剂的能力，如白藜芦醇（RES）或新型重组线粒体含锰超氧化物歧化酶（rMnSOD）或δ-生育三烯酚（δ-TOCO），与 DAS 和 NIL 相互作用对活力、活性氧（ROS）产生、脂质过氧化和细胞凋亡的影响。为了测试这些抗氧化剂的可能作用机制，我们利用 N-乙酰-L-半胱氨酸（NAC），一种特异性的 ROS 产生抑制剂，或 PP1，一种特异性的Src 酪氨酸激酶抑制剂，或 BAPTA，一种特异性的细胞内钙螯合剂。我们的数据表明：1）RES、rMnSOD、δ-TOCO 和 NAC 在使用剂量下，显著降低了 DAS 或 NIL 诱导的 MDA 的细胞内水平；2）RES、rMnSOD 和 δ-TOCO 增加了细胞内的 ROS 水平；3）ROS 水平的增加与 DAS 和 NIL 诱导的更高水平的寡核苷酸有关，而 NAC 显著降低了这种活性。有趣的是，我们的数据表明，DAS 和 NIL 的促凋亡活性通过触发过量的 ROS 生成以及 SERCA 受体的功能，显著增加了 DAS 和 NIL 诱导的寡核苷酸的产生。
