The insect repellent N,N-diethyl-m-toluamide (DEET) induces angiogenesis via allosteric modulation of the M3 muscarinic receptor in endothelial cells

Abstract

The insect repellent N,N-diethyl-m-toluamide (DEET) has been reported to inhibit AChE (acetylcholinesterase) and to possess potential carcinogenic properties with excessive vascularization. In the present paper, we demonstrate that DEET specifically stimulates endothelial cells that promote angiogenesis which increases tumor growth. DEET activates cellular processes that lead to angiogenesis including proliferation, migration and adhesion. This is associated with an enhancement of NO production and VEGF expression in endothelial cells. M3 silencing or the use of a pharmacological M3 inhibitor abrogates all of these effects which reveals that DEET-induced angiogenesis is M3 sensitive. The experiments involving calcium signals in both endothelial and HEK cells overexpressing M3 receptors, as well as binding and docking studies demonstrate that DEET acts as an allosteric modulator of the M3 receptor. In addition, DEET inhibited AChE which increased acetylcholine bioavailability and binding to M3 receptors and also strengthened proangiogenic effects by an allosteric modulation.

Olfactory Mechanisms for Discovery of Odorants to Reduce Insect-Host Contact

“…These two attributes make it one of the most commonly used insect repellents in the developed world. However DEET has also been shown to dissolve nylons and plastics, blocks human acetylcholinesterase, activates human M3 muscarinic GPCR causing anti-angiogenesis, inhibits mammalian TRPM8, and inhibits mammalian CNGA2 channels, the health consequences of none of which are well understood (Abd-Ella 2015; Corbel 2009; Ditzen 2008; Legeay 2016; Swale 2015). The notion that identification of the mechanisms of action of DEET could help in the development of improved broad-spectrum repellents has resulted in much recent research in this area (Ray 2015).…”

Topological QSAR Modelling of Carboxamides Repellent Activity to Aedes Aegypti

“…The studied carboxamides (of general formula R 1 ‐CO‐NR 2 R 3 ) correspond only to a very scarce number of the possble combinations of the R 1 and NR 2 R 3 radicals investigated. One interest of the full model proposed above (equation 1) is to provide at a screening level the estimation of the activity of new alternatives to DEET, which has been associated to multiple undesired effects to human and the environment . For example, with in mind the similar activity of radicals N(C 2 H 5 ) (C 4 H 11 ) and cyclo (NC 6 H 12 ), listed in Table , we have estimated, with MLR, the potential activity of 4 new compounds with structure R 1 ‐CO−Cyclo(NC 6 H 12 ) where R 1 is respectively CH(C 2 H 5 ) 2 , iBu, 2 Me−C 6 H 4 and C 3 H 6 C≡CH.…”

“…However, its use has been related to adverse effects in humans. A recent study by Legeay, S. et al . suggests pro‐angiogenic properties in humans and highlights the need to implement human risk assessment, to secure safe use of DEET‐based products.…”

Is DEET a dangerous neurotoxicant?

“…Another recent study found that DEET was an allosteric modulator of muscarinic acetylcholine receptors, another possible GPCR target for DEET, and it was hypothesized that such an action might potentiate the effects of carbamate insecticides in insects . Further, DEET may modulate M 3 receptors in endothelial cells to affect angiogenesis, including proliferation, migration and adhesion . How predictive these studies might be for any in vivo toxicological effect of DEET to human users requires further study.…”