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

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.

α-Conotoxins and α-Cobratoxin Promote, while Lipoxygenase and Cyclooxygenase Inhibitors Suppress the Proliferation of Glioma C6 Cells

“…This suggests that 12-LOX plays a significant role in the survival and especially in the proliferative activity of C6 glioma cells. Earlier, we observed similar effects of LOX inhibitors in the Ehrlich’s ascites carcinoma cells [ 20 ]. Unexpectedly, our data ( Figure 5 c) show that the selective COX-2 inhibitor NS-398 reduced the antiproliferative effect of NDGA.…”

“…Thus, epidemiological studies show that the agonists of these receptors, nicotine and its derivatives contained in tobacco smoke, contribute to the onset and development of tumors of the lung [ 1 ], breast [ 3 , 63 ], pancreas [ 64 , 65 ], head and neck [ 66 ], accelerating proliferation and suppressing apoptosis. On the contrary, blockade of nAChRs slows tumor growth in experimental models of lung [ 21 , 22 ] and breast [ 18 , 20 ] cancer. The effect of nicotine is realized with the participation of nAChRs containing α7 [ 1 , 67 ], α9 [ 1 , 15 , 68 ] and α5 [ 1 , 2 , 16 ] subunits.…”

“…The role of nAChRs in non-neuronal cells is a subject of extensive studies, but it is already clear that these receptors are involved in the regulation of proliferation and migration of cancer cells [ 13 , 14 ], promote tumor formation [ 15 ] and enhance the resistance of tumor cells to apoptosis [ 14 , 16 , 17 ]. In addition, a number of experimental studies have shown a slowdown in tumor growth in vivo under the action of nAChR blockers such as α-conotoxins [ 18 , 19 , 20 ], α-cobrotoxin [ 21 ] and alkylpyridinium polymer APS8 [ 22 ]. However, the cytotoxic properties of nicotine, agonist of the most of nAChRs, against both normal [ 23 , 24 , 25 , 26 ] and tumor [ 27 ] cells are known.…”

“…To study possible involvement of these receptors in survival and proliferation of glioma C6 cells, we chose the animal toxins that specifically block distinct nAChR subtypes. We have previously shown that the combined use of α-conotoxins, nAChR blockers, and COX and LOX inhibitors promotes the death of Ehrlich carcinoma cells in vitro and slows tumor growth in vivo [ 20 ]. It should be noted that Ehrlich ascites carcinoma has a non-neuronal origin and is a spontaneous murine mammary adenocarcinoma.…”

Interaction of α9α10 Nicotinic Receptors With Peptides and Proteins From Animal Venoms

“…The anticancer activity of several nAChR subtype selective α-conotoxins was also tested ( Terpinskaya et al, 2015 , 2020 ). The application of α-conotoxins PnIA, RgIA, ArIB[V11L,V16D], or MII together with either baicalein or indomethacin to Ehrlich carcinoma enhanced the antitumor activity several-fold ( Osipov et al, 2020 ). However, while baicalein exerted antiproliferative and cytotoxic effects also on C6 glioma cells, α-Ctx and α-conotoxin RgIA on the contrary promoted proliferation of these cells ( Terpinskaya et al, 2021 ).…”