α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors.

Alexey V Osipov,Maxim N Zhmak,Victor I Tsetlin,Tatjana Balashevich,Tatiana I Terpinskaya,Yuri N Utkin,Tatsiana Yanchanka

doi:10.3390/md18040193

Abstract

Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3β2/α6β2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8–3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3β2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors.

Highlights

Tumor cells are characterized by the increased activity of some biochemical pathways that promote their survival and proliferation
We have previously shown that some α-conotoxins can inhibit the development of Ehrlich carcinoma, the most active being α-conotoxin MII [7]
The indomethacin, a non-selective COX inhibitor, did not affect the cell viability after incubation for 24 h, and after 48 h it decreased the viability by 20%. α-Conotoxin MII enhanced this indomethacin effect by increasing the number of dead cells 1.9-fold (Figure 1)

Summary

Introduction

Tumor cells are characterized by the increased activity of some biochemical pathways that promote their survival and proliferation. One of these pathways is the arachidonic acid cascade: arachidonate is released from the phospholipids of the cell membrane and transformed into eicosanoids. Among the latter are prostanoids (prostaglandins and thromboxanes) formed with the participation of cyclooxygenases (COX), and leukotrienes formed with the participation of lipoxygenases (LOX). The tumor-promoting effect of COX is associated with the increased PGE2 synthesis, which has an immunosuppressive effect [1] and plays an important role in the growth and progression of tumors. Leukotriene B4 and hydroxyeicosotetraenoic acids (HETE), such as 5S-HETE and

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Conclusion