Morphine may be harmful in patients with angiogenesis-dependent cancers.

PMID: 

Clin Exp Pharmacol Physiol. 2019 Oct 15. Epub 2019 Oct 15. PMID: 31612523

Abstract Title: 

Morphine stimulates angiogenesis through Akt/mTOR/eIF4E activation under serum deprivation or HO-induced oxidative stress condition.

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 tumor angiogenesis under serum deprivation and HO-induced oxidative stress conditions. We found that morphine protected human lung tumor associated-endothelial cell (HLT-EC) against serum deprivation or HO-induced inhibition of capillary network formation. Furthermore, morphine stimulated other biological functions of HLT-EC under serum deprivation and HO-induced pathological conditions, such as growth, migration and survival, without affecting HLT-EC adhesion. Interestingly, morphine at the same concentration did not affect lung tumor cell growth and survival, suggesting the specific protective role of morphine at low micromolar concentrations on tumor angiogenesis. Using in vivo Matrigel angiogenesis assay, we found that morphine stimulated in vivo angiogenesis under HO-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 HO-induced angiogenesis inhibition via reducing oxidative stress and damage, and activating Akt/mTOR/eIF4E signaling. We demonstrate the protective role of morphine on tumor angiogenesis under pathological conditions. Our work suggests that clinical use of morphine may be harmful in patients with angiogenesis-dependent cancers.

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