Voltage-Gated K+/Na+ Channels and Scorpion Venom Toxins in Cancer

Abstract

Ion channels have recently been recognized as novel therapeutic targets in cancer research since they are overexpressed in different histological tissues, and their activity is linked to proliferation, tumor progression, angiogenesis, metastasis, and apoptosis. Voltage gated-potassium channels (VGKC) are involved in cell proliferation, cancer progression, cell cycle transition, and apoptosis. Moreover, voltage-dependent sodium channels (VGSC) contribute to decreases in extracellular pH, which, in turn, promotes cancer cell migration and invasion. Furthermore, VGSC and VGKC modulate voltagesensitive Ca 2+ channel activity by controlling the membrane potential and regulating Ca 2+ influx, which functions as a second messenger in processes related to proliferation, invasion, migration, and metastasis. The subgroup of these types of channels that have shown a high oncogenic potential have become known as "oncochannels", and the evidence has highlighted them as key potential therapeutic targets. Scorpion venoms contain a high proportion of peptide toxins that act by modulating voltage-gated Na + /K + channel activity. Increasing scientific data have pointed out that scorpion venoms and their toxins can affect the activity of oncochannels, thus showing their potential for anticancer therapy. In this review, we provide an update of the most relevant voltage-gated Na + \K + ion channels as cellular targets and discuss the possibility of using scorpion venom and toxins for anticancer therapy.

Targeting mitochondrial ion channels for cancer therapy

“…Some of these target ion channels known to be present also in mitochondria. The best known are the high-affinity peptide inhibitors of K + channels of the Kv, KCa, K2P families [ [235] , [236] , [237] , [238] ]. These peptides may help in the characterization of the various conductances found in the MIM, but they are not in use to modulate intracellular channels in cultured cells, ex-vivo preparations or in vivo , because they do not permeate cell membranes.…”

Effects of carbamazepine in aquatic biota

“…Ion channels are instrumental for the regulation of cellular homeostasis, involved in diverse physiological processes, including electrical signal transmission, gene expression, cell signaling pathways, hormonal secretion. 39 Data thus suggested a detrimental effect of CBZ on cell signaling with very diverse potential consequences for fitness of biota.…”

Voltage-Gated Potassium Channels as Regulators of Cell Death

“…This situation is most probably due to our limitation of having promiscuous pharmacological inhibitors as tools to modulate the function of these channels. Nonetheless, the use of toxins, small molecules and specific antibodies is emerging as promising strategy (for recent review see e.g., Wulff et al, 2019 ; Díaz-García and Varela, 2020 ).…”

“…It reduced the potassium current with an IC 50 value of 10 μM, suppressed proliferation and migration of hepatoma cells and inhibited tumor growth in vivo in a xenograft model of liver cancer ( Na et al, 2020 ). In addition, the only Kv10.1-specific toxin, k-Hefutoxin 1 from Heterometrus fulvipes scorpion venom ( Moreels et al, 2017 ), might be useful in the context of cancer therapy, but to our knowledge no attempts have been made so far to test its in vitro and in vivo effects ( Díaz-García and Varela, 2020 ).…”

“…In addition, toxins might offer a way of intervention: CsEKerg1 toxin, from the Centruroides sculpturatus scorpion, inhibits Kv11.1 currents in neuroblastoma cells, although with relatively low affinity ( Nastainczyk et al, 2002 ). Unfortunately, this toxin has not been tested on brain-derived tumor cell proliferation ( Díaz-García and Varela, 2020 ).…”