A new matrix metalloproteinase inhibitor SI-27 induces apoptosis in several human myeloid leukemia cell lines and enhances sensitivity to TNF alpha-induced apoptosis.
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 (deltapsim), presence of hypodiploid DNA, and cleavage of PARP and IkappaBalpha. Furthermore, at lowered concentrations, which did not directly induce apoptosis, SI-27 acted to sensitize U937 cells and other cells to tumor necrosis factor alpha (TNF-alpha)-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.
Nakamura
Y
Y
Third Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Sato
K
K
Wakimoto
N
N
Kimura
F
F
Okuyama
A
A
Motoyoshi
K
K
D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D009842:Oligopeptides; D011480:Protease Inhibitors; C421267:SI 27; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases