Hallak Maher, Danilenko Michael, Win Thida, Bittner Shmuel, Granot Yosef, Shpilberg Ofer, Levi Itai, Nathan Ilana
Institute of Hematology, Soroka University Medical Center, Beer Sheva, Israel.
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 8410501, Beer Sheva, Israel.
Mol Cell Biochem. 2023 Feb;478(2):393-406. doi: 10.1007/s11010-022-04514-0. Epub 2022 Jul 14.
Novel derivatives of aminophenyl-1,4-naphthoquinones, in which a pyrrolidine group was added to the naphthoquinone ring, were synthesized and investigated for the mechanisms of leukemic cell killing. The novel compounds, TW-85 and TW-96, differ in the functional (methyl or hydroxyl) group at the para-position of the aminophenyl moiety. TW-85 and TW-96 were found to induce concentration- and time-dependent apoptotic and/or necrotic cell death in human U937 promonocytic leukemia cells but only TW-96 could also kill K562 chronic myeloid leukemia cells and CCRF-CEM lymphoblastic leukemia cells. Normal peripheral blood mononuclear cells were noticeably less responsive to both compounds than leukemia cells. At low micromolar concentrations used, TW-85 killed U937 cells mainly by inducing apoptosis. TW-96 was a weaker apoptotic agent in U937 cells but proved to be cytotoxic and a stronger inducer of necrosis in all three leukemic cell lines tested. Both compounds induced mitochondrial permeability transition pore opening, cytochrome c release, and caspase activation in U937 cells. Cytotoxicity induced by TW-96, but not by TW-85, was associated with the elevation of the cytosolic levels of reactive oxygen species (ROS). The latter was attenuated by diphenyleneiodonium, indicating that NADPH oxidase was likely to be the source of ROS generation. Activation of p38 MAPK by the two agents appeared to prevent necrosis but differentially affected apoptotic cell death in U937 cells. These results further expand our understanding of the structure-activity relationship of aminophenyl-1,4-naphthoquinones as potential anti-leukemic agents with distinct modes of action.
合成了氨基苯基 - 1,4 - 萘醌的新型衍生物，其中在萘醌环上添加了吡咯烷基，并对其杀死白血病细胞的机制进行了研究。新型化合物TW - 85和TW - 96在氨基苯基部分对位的官能团（甲基或羟基）上有所不同。研究发现，TW - 85和TW - 96可在人U937原单核细胞白血病细胞中诱导浓度和时间依赖性的凋亡和/或坏死性细胞死亡，但只有TW - 96还能杀死K562慢性髓性白血病细胞和CCRF - CEM淋巴细胞白血病细胞。正常外周血单核细胞对这两种化合物的反应明显低于白血病细胞。在低微摩尔浓度下，TW - 85主要通过诱导凋亡杀死U937细胞。TW - 96在U937细胞中是一种较弱的凋亡诱导剂，但在所有三种测试的白血病细胞系中均被证明具有细胞毒性且是更强的坏死诱导剂。两种化合物均在U937细胞中诱导线粒体通透性转换孔开放、细胞色素c释放和半胱天冬酶激活。TW - 96而非TW - 85诱导的细胞毒性与胞质活性氧（ROS）水平升高有关。后者被二苯基碘鎓减弱，表明NADPH氧化酶可能是ROS产生的来源。两种药物对p38 MAPK的激活似乎可预防坏死，但对U937细胞凋亡性细胞死亡的影响存在差异。这些结果进一步扩展了我们对氨基苯基 - 1,4 - 萘醌作为具有不同作用模式的潜在抗白血病药物的构效关系的理解。
