Abstract
Opioids are effective analgesics for the management of moderate to severe cancer pain. Here we show that κ opioid receptor (KOR) agonists act as anti-angiogenic factors in tumors. Treatment with KOR agonists, U50,488H and TRK820, significantly inhibited human umbilical vein endothelial cell (HUVEC) migration and tube formation by suppressing VEGFR2 expression. In contrast, treatment with a μ opioid receptor agonist, DAMGO, or a δ opioid receptor agonist, SNC80, did not prevent angiogenesis in HUVECs. Lewis lung carcinoma (LLC) or B16 melanoma grafted in KOR knockout mice showed increased proliferation and remarkably enhanced tumor angiogenesis compared with those in wild type mice. On the other hand, repeated intraperitoneal injection of TRK820 (0.1–10 μg/kg, b.i.d.) significantly inhibited tumor growth by suppressing tumor angiogenesis. These findings indicate that KOR agonists play an important role in tumor angiogenesis and this knowledge could lead to a novel strategy for cancer therapy.
Highlights
Opioids are effective analgesics for the management of moderate to severe cancer pain
Both U50,488H and TRK820, but not DAMGO or SNC80, dramatically inhibited human umbilical vein endothelial cell (HUVEC) tube formation (Fig. 1d, e). These effects on tube formation were inhibited by knockdown of k opioid receptor (KOR) with siRNA (Supplemental Fig. 1e). These findings indicate that KOR signaling could regulate angiogenesis in vitro
Since k opioids could act as inhibitors of tumor angiogenesis, we considered the possibility of tumor therapy with KOR agonists
Summary
Opioids are effective analgesics for the management of moderate to severe cancer pain. On the other hand, repeated intraperitoneal injection of TRK820 (0.1–10 mg/kg, b.i.d.) significantly inhibited tumor growth by suppressing tumor angiogenesis These findings indicate that KOR agonists play an important role in tumor angiogenesis and this knowledge could lead to a novel strategy for cancer therapy. We showed that k opioid peptides acted as novel anti-angiogenic modulators through suppressing the www.nature.com/scientificreports expression of VEGF receptors, VEGFR2 and Neuropilin[1], during vascular differentiation via inhibition of cAMP/PKA signaling[13]. We first demonstrated that KOR agonists have a potential as anti-tumor angiogenic modulators by inhibiting VEGFR2 expression These findings support a novel strategy for tumor therapy as well as the relief of cancer pain
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