Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Abstract

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 M-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 f100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC 50 of 5-FU from f5 Mmol/L to f7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC 50 of bevacizumab on inhibition of EC migration from f25 to f6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary M-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase M activity, which was independent of M-opioid receptor expression. Silencing receptor protein tyrosine phosphatase M 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.

O papel dos antagonistas periféricos dos opióides no tratamento da dor e nos cuidados perioperatórios

“…Further, the model system predicted a synergy between chemotherapeutic agents and MNTX beyond the receptor level. A potentiation of MNTX on the anti-angiogenic effects of chemotherapeutic agents 5FU and bevacizumab has been reported in pulmonary endothelial cells 45 . Recent in vitro studies have determined that pseudomonas have mu opiate receptors that produce the lethality factors procyanin and PA-1L.…”

“…Além disso, o modelo previu sinergia entre os agentes quimioterápicos e a MNTX além do nível do receptor. Relatou-se potencialização da MNTX nos efeitos antiangiogênicos dos quimioterápicos 5FU e bevacizumabe nas células endoteliais pulmonares 45 . Estudos in vitro recentes determinaram que pseudomonas têm receptores opióides mu que produzem os fatores de letalidade procianidina e PA-1L que são bloqueados pela MNTX, sugerindo efeito dos opióides na sépsis bacteriana que pode ser influenciada pelos antagonistas 46 .…”

Development and use of methylnaltrexone, a peripherally acting opioid antagonist, to treat side effects related to opioid use

“…One hypothesis is that epidural anesthesia confers a protective effect directly or indirectly (through attenuation of a stress response), an alternative explanation is that endogenous and exogenous opioids during surgery may change endothelial permeability [Singleton et al, 2007]. Additionally a recent report showed synergistic effects of methylnaltrexone with 5-FU and bevacizumab on inhibition of VEGF-induced angiogenesis [Singleton et al, 2008] even in the absence of opioids.…”

Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone

“…Μu-type opioid receptors are identified in several immunological cell subsets [25,26], and it has been demonstrated that opioids suppress T cell functioning and the production of several cytokines [23,27-29]. Activation of the μ-opioid receptor expressed on endothelial cells stimulates angiogenesis and a synergistic effect of morphine sulphate with VEGF has been demonstrated [21,30,31]. Methylnaltrexone could be of additive value to prevent this unwanted immunomodulatory and angiogenic activity of opioids [30].…”

“…Activation of the μ-opioid receptor expressed on endothelial cells stimulates angiogenesis and a synergistic effect of morphine sulphate with VEGF has been demonstrated [21,30,31]. Methylnaltrexone could be of additive value to prevent this unwanted immunomodulatory and angiogenic activity of opioids [30]. Therefore, we will study the effects of methylnaltrexone on immunomodulatory and angiogenic activity in patients during treatment with this agent.…”