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.