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Morphine stimulates angiogenesis through Akt/mTOR/eIF4E activation under serum deprivation or H 2 O 2 ‐induced oxidative stress condition
Author(s) -
Zhang Kun,
Huang Wei,
Chen Wei,
Zhou Qian,
Zhang Qiongxia,
Wu Xiaoqin,
Xu Yong,
Li Dezhan,
Xie Tao,
Liu Jie
Publication year - 2020
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13191
Subject(s) - angiogenesis , morphine , pharmacology , pi3k/akt/mtor pathway , opioid , chemistry , oxidative stress , protein kinase b , opioid receptor , neovascularization , (+) naloxone , in vivo , cancer research , medicine , apoptosis , receptor , endocrinology , biology , biochemistry , microbiology and biotechnology
Abstract Morphine is an opioid analgesic drug routinely used to treat pain in several medical conditions including cancer. Increasing evidence has shown that morphine can directly modulate cancer growth via regulating angiogenesis. In this work, we investigated the effect of morphine on angiogenesis under pathological conditions. We showed that morphine, in a concentration typical of that observed in patient's blood, stimulates tumour angiogenesis under serum deprivation and H 2 O 2 ‐induced oxidative stress conditions. We found that morphine protected human lung tumour associated‐endothelial cell (HLT‐EC) against serum deprivation or H 2 O 2 ‐induced inhibition of capillary network formation. Furthermore, morphine stimulated other biological functions of HLT‐EC under serum deprivation and H 2 O 2 ‐induced pathological conditions, such as growth, migration and survival, without affecting HLT‐EC adhesion. Interestingly, morphine at the same concentration did not affect lung tumour cell growth and survival, suggesting the specific protective role of morphine at low micromolar concentrations on tumour angiogenesis. Using in vivo Matrigel angiogenesis assay, it was found that morphine stimulated in vivo angiogenesis under H 2 O 2 ‐induced pathological condition. The opioid receptor antagonist, naloxone, did not inhibit the protective activity of morphine in in vivo angiogenesis, indicating that the effect was less likely to be mediated by the typical opioid receptors. Mechanism analysis indicated that morphine alleviated serum deprivation and H 2 O 2 ‐induced angiogenesis inhibition via reducing oxidative stress and damage, and activating Akt/mTOR/eIF4E signalling. We demonstrate the protective role of morphine on tumour angiogenesis under pathological conditions. Our work suggests that clinical use of morphine may be harmful in patients with angiogenesis‐dependent cancers.