A new matrix metalloproteinase inhibitor SI-27 induces apoptosis in several human myeloid leukemia cell lines and enhances sensitivity to TNF alpha-induced apoptosis
A new matrix metalloproteinase inhibitor SI-27 induces apoptosis in several human myeloid leukemia cell lines and enhances sensitivity to TNF alpha-induced apoptosis
复制标题
新型基质金属蛋白酶抑制剂 SI-27 诱导多种人髓性白血病细胞系凋亡，并增强对 TNF α 诱导的细胞凋亡的敏感性
作者：
Y. Nakamura;K. Sato;N. Wakimoto;F. Kimura;A. Okuyama;K. Motoyoshi
MMP抑制剂在临床上用于稳定肿瘤生长，从而延长癌症患者的生存期。然而，它们在治疗造血恶性肿瘤中的作用尚不清楚。在本研究中，我们研究了一种新的MMP抑制剂SI-27在造血恶性肿瘤中的作用。SI-27单独通过激活caspase 8、9和3诱导几种人髓性白血病细胞系如U937、NB4和HL60细胞凋亡。通过膜联蛋白V阳性染色、线粒体跨膜电位下降（ΔΨm）、次二倍体DNA的存在以及PARP和i - κ b α的切割来检测细胞凋亡。此外，在不直接诱导细胞凋亡的低浓度下，SI-27可以使U937细胞和其他细胞对肿瘤坏死因子α (TNF-α)介导的细胞凋亡敏感。由于暴露于SI-27，膜Fas、Fas配体和TNFR1的积累不明显，拮抗Fas或抗Fas配体抗体不能阻断SI-27诱导的细胞凋亡。因此，si -27诱导的细胞凋亡不是通过Fas途径介导的。这些结果表明，MMP抑制剂单独或与其他细胞毒性药物联合使用，可以为治疗经典抗癌药物难治性急性髓系白血病提供一种独特的方法，并可能因此抑制复发。
MMP inhibitors are used clinically for the stabilization of tumor growth, thus prolonging survival in cancer patients. However, their role in the treatment of hematopoietic malignancies remains unclear. In the present study, we investigated the effects of a new MMP inhibitor, SI-27, in hematopoietic malignancies. SI-27 alone induces apoptosis in several human myeloid leukemia cell lines such as U937, NB4, and HL60 cells by activating caspase 8, 9, and 3. Apoptosis was measured with annexin V positive staining, a drop in mitochondrial transmembrane potential (ΔΨm), presence of hypodiploid DNA, and cleavage of PARP and IκBα. Furthermore, at lowered concentrations, which did not directly induce apoptosis, SI-27 acted to sensitize U937 cells and other cells to tumor necrosis factor α (TNF-α)-mediated apoptosis. The accumulation of membrane Fas, the Fas ligand, and TNFR1 were not apparent due to exposure to SI-27, and antagonistic anti-Fas or anti-Fas ligand antibodies did not block SI-27-induced apoptosis. Thus, SI-27-induced apoptosis is not mediated by the Fas pathway. These results suggest that MMP inhibitors, alone or in combination with other cytotoxic agents, can provide a unique method for treating acute myeloid leukemia, refractory to classical anti-cancer drugs, and may thus suppress recurrence.
影响因子：
158.5
作者：
MAYER, RJ;DAVIS, RB;FREI, E
通讯作者：
FREI, E
影响因子：
20.3
作者：
Eischen, CM;Kottke, TJ;Kaufmann, SH
通讯作者：
Kaufmann, SH
影响因子：
45.3
作者：
Wojtowicz-Praga, S;Torri, J;Hawkins, MJ
通讯作者：
Hawkins, MJ