Many patients with
cancer receive combinations of
drug treatments that include
5-fluorouracil (5-FU) and
bevacizumab. Therapeutic doses of
5-FU are often associated with unwanted side effects, and
bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that
methylnaltrexone (MNTX), a peripheral antagonist of the
mu-opioid receptor, exerts a synergistic effect with
5-FU and
bevacizumab on inhibition of
vascular endothelial growth factor (
VEGF)-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in
cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC(50) of approximately 100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC(50) of
5-FU from approximately 5 micromol/L to approximately 7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC(50) of
bevacizumab on inhibition of EC migration from approximately 25 to approximately 6 ng/mL. These synergistic effects were not observed with
naltrexone, a tertiary
mu-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not
naltrexone, increased
receptor protein tyrosine phosphatase mu activity, which was independent of
mu-opioid receptor expression. Silencing
receptor protein tyrosine phosphatase mu expression (
small interfering RNA) in human EC inhibited both synergy between MNTX and
bevacizumab or
5-FU and increased
VEGF-induced
tyrosine phosphorylation of Src and p190
RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory
protein, RhoA, whereas silencing Src, Akt, or RhoA blocked
VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of
5-FU and
bevacizumab, which could improve index.