Previous studies from our group have demonstrated in vitro that
UCN-01 (7-hydroxystaurosporine) and inhibitors of MEK1/2 interact to cause
tumor cell death in a wide variety of malignant, but not in nontransformed, cell types. The present studies determined whether
UCN-01 and MEK1/2 inhibitors interacted to cause
tumor cell death in vivo. In vitro colony formation studies demonstrated that
UCN-01 and the MEK1/2 inhibitor
PD184352 interacted to synergistically kill
human mammary carcinoma cells (MDA-MB-231, MCF7) with similar combination index values. Athymic mice were implanted in the rear flank with either MDA-MB-231 or MCF7 cells and
tumors permitted to form to a volume of approximately 100 mm3 prior to a two day exposure of either Vehicle,
PD184352 (25 mg/kg),
UCN-01 (0.1-0.2 mg/kg) or the
drug combination.
Tumor volume was measured every other day and
tumor growth determined over the following approximately 30 days. Transient exposure of MDA-MB-231
tumors or MCF7
tumors to either
PD184352 or
UCN-01 did not significantly alter
tumor growth rate or the mean
tumor volume in vivo approximately 15-30 days after
drug administration. In contrast, combined treatment with
PD184352 and
UCN-01 significantly reduced MDA-MB-231, and largely abolished MCF7
tumor growth.
Tumor control values for both cell lines were 0.36.
Tumor cells isolated approximately 30 days after combined
drug exposure exhibited a significantly greater reduction in plating efficiency using ex vivo colony formation assays than
tumor cells that were exposed to either
drug individually. Reduced
tumor growth correlated with profound
tumor cell death within five days of combined
drug exposure, which was also evident approximately 30 days after exposure. In addition,
tumor cell death correlated with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. Collectively, these findings argue that
UCN-01 and MEK1/2 inhibitors have the potential to suppress mammary
tumor growth in vivo which is independent of p53 status,
estrogen dependency,
caspase 3 levels or oncogenic K-RAS expression.