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. 2021 Mar 29;13(7):1576. doi: 10.3390/cancers13071576

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© 2021 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Effects of anticancer drugs and flavonoids at the peripheral nociceptor. (a) Simplified Overview. Flavonoids counter anticancer drug induced nociceptor sensitization. Anticancer drugs, via the enhanced release of proinflammatory cytokines and activation of ion channels, sensitize the nociceptor, increasing the likelihood that the membrane potential will reach the threshold potential. Thus, there is a greater chance that action potentials will result from weak stimuli that under normal conditions would not reach the threshold potential. (b) Effects of anticancer drugs on the peripheral nociceptor. Anticancer drugs increase the release of proinflammatory mediators such as TNF-α, IL-1β, IL-6, and histamine. These mediators directly sensitize ion channels and activate the ERK/JNK and p38/MAPK pathways, resulting in the activation of Na^+1.8 and Na^+1.9 and the inhibition of K^+v. Histamine, prostaglandins, and tryptase bind to their respective receptors and activate the PKA and PKC pathways, which increase the membrane density of TRPV1 and Na⁺ _v channels. These events ultimately elevate the membrane potential to the threshold value, increasing the likelihood of an action potential; (c) Actions of flavonoids counter anticancer drugs’ effects. Icariin and trimethoxy and dimethoxy flavones decrease the release of TNF-α, IL-1β, and IL-6 from astrocytes, microglia, and the DRG, and thereby downregulate the ERK/JNK and p38/MAPK pathways. This reduces the membrane density of ion channels, and consequently decreases the likelihood of reaching the threshold potential and reduces pain signal transmission; (d) Activation of PKA and PKC derivatives by anticancer drugs. Paclitaxel induces the degranulation of mast cells, which release tryptase and other proinflammatory mediators. Tryptase acts on PAR2, leading to PKA activation, the sensitization of TRPV1, TRPA1, and TRPV4, and the increased membrane fusion of Na⁺ _v. The sensitization of TRP channels increases Na⁺ and Ca²⁺ inflow into the nociceptor. Ca²⁺ causes vesicles to fuse with the membrane and activates PKCδ, CaMKII, and PKC∈, which activate TRPV4 and TRPV1, further increasing ion inflow. These events increase the likelihood that the membrane potential will reach the threshold potential; (e) Flavonoids prevent neuropathic pain, affecting PKA and PKC derivatives activation. Quercetin inhibits the translocation of PKC∈ from the cytoplasm to the membrane and prevents paclitaxel-induced mast cell degranulation. Thus, there is less activation of PKA and PKC derivatives, which leads to decreased channel activation, less ionic influx, and a reduced likelihood that the membrane potential will reach threshold potential; (f) Anticancer drugs lead to the release of proinflammatory cytokines, which sensitize the nociceptor. Proinflammatory cytokines act directly on and sensitize TRP channels. They also increase the phosphorylation of transcription factors in the DRG via the p38/MAPK, ERK, and JNK pathways, increasing the synthesis of primary afferent channels; (g) Flavonoids (icariin and trimethoxy and dimethoxy flavones) reduce the release of proinflammatory cytokines by astrocytes, microglia, and the DRG. Thus, they downregulate the p38/MAPK, ERK, and JNK pathways, decrease ion channel density and phosphorylation, and consequently decrease the likelihood that the membrane potential will reach the threshold potential.

Effects of anticancer drugs and flavonoids at the peripheral nociceptor. (a) Simplified Overview. Flavonoids counter anticancer drug induced nociceptor sensitization. Anticancer drugs, via the enhanced release of proinflammatory cytokines and activation of ion channels, sensitize the nociceptor, increasing the likelihood that the membrane potential will reach the threshold potential. Thus, there is a greater chance that action potentials will result from weak stimuli that under normal conditions would not reach the threshold potential. (b) Effects of anticancer drugs on the peripheral nociceptor. Anticancer drugs increase the release of proinflammatory mediators such as TNF-α, IL-1β, IL-6, and histamine. These mediators directly sensitize ion channels and activate the ERK/JNK and p38/MAPK pathways, resulting in the activation of Na^+1.8 and Na^+1.9 and the inhibition of K^+v. Histamine, prostaglandins, and tryptase bind to their respective receptors and activate the PKA and PKC pathways, which increase the membrane density of TRPV1 and Na⁺ _v channels. These events ultimately elevate the membrane potential to the threshold value, increasing the likelihood of an action potential; (c) Actions of flavonoids counter anticancer drugs’ effects. Icariin and trimethoxy and dimethoxy flavones decrease the release of TNF-α, IL-1β, and IL-6 from astrocytes, microglia, and the DRG, and thereby downregulate the ERK/JNK and p38/MAPK pathways. This reduces the membrane density of ion channels, and consequently decreases the likelihood of reaching the threshold potential and reduces pain signal transmission; (d) Activation of PKA and PKC derivatives by anticancer drugs. Paclitaxel induces the degranulation of mast cells, which release tryptase and other proinflammatory mediators. Tryptase acts on PAR2, leading to PKA activation, the sensitization of TRPV1, TRPA1, and TRPV4, and the increased membrane fusion of Na⁺ _v. The sensitization of TRP channels increases Na⁺ and Ca²⁺ inflow into the nociceptor. Ca²⁺ causes vesicles to fuse with the membrane and activates PKCδ, CaMKII, and PKC∈, which activate TRPV4 and TRPV1, further increasing ion inflow. These events increase the likelihood that the membrane potential will reach the threshold potential; (e) Flavonoids prevent neuropathic pain, affecting PKA and PKC derivatives activation. Quercetin inhibits the translocation of PKC∈ from the cytoplasm to the membrane and prevents paclitaxel-induced mast cell degranulation. Thus, there is less activation of PKA and PKC derivatives, which leads to decreased channel activation, less ionic influx, and a reduced likelihood that the membrane potential will reach threshold potential; (f) Anticancer drugs lead to the release of proinflammatory cytokines, which sensitize the nociceptor. Proinflammatory cytokines act directly on and sensitize TRP channels. They also increase the phosphorylation of transcription factors in the DRG via the p38/MAPK, ERK, and JNK pathways, increasing the synthesis of primary afferent channels; (g) Flavonoids (icariin and trimethoxy and dimethoxy flavones) reduce the release of proinflammatory cytokines by astrocytes, microglia, and the DRG. Thus, they downregulate the p38/MAPK, ERK, and JNK pathways, decrease ion channel density and phosphorylation, and consequently decrease the likelihood that the membrane potential will reach the threshold potential.