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Page 10 of 16 Chávez-López et al. Hepatoma Res 2020;6:14 I http://dx.doi.org/10.20517/2394-5079.2019.023

Table 2. Ion channel inhibitors as potential therapeutic agents studied in HCC
Inhibitor Targeted ion channel Ion channel gene symbol * Ref.
TRAM-34 K Ca3.1 KCNN4 [103,104]
ASTEMIZOLE Eag1, Herg KCNH1, KCNH2 [115]
2+
MIBEFRADIL T-type Ca channels -- [117]
2-APB, SKF96365 SOCs -- [21,118,121]
DIDS CIC-3 CLCN3 [122]
MicroRNA-325-3P AQP5 AQP5 [126]
CAPSAICIN TRPV1 TRPV1 [135]
HC-067047 TRPV4 TRPV4 [137]
*When the specific ion channel has been reported to be targeted. HCC: hepatocellular carcinoma

Table 3. Ion channels suggested as HCC prognostic markers
Channel Gene symbol Expression in HCC Association to prognosis Ref.
KCNQ1 KCNQ1 Downregulated Poor prognosis [105]
KCNJ11 KCNJ11 Differentially expressed Poor prognosis [106]
P2X3 P2RX3 Overexpression Poor recurrence-free survival [119]
TRPV1 TRPV1 Overexpression Better prognosis [134]
ASIC1a ASIC1 Overexpression Advanced clinical stage [139]
ITPR3 ITPR3 Overexpression Poor survival [141]
HCC: hepatocellular carcinoma

liver. Thus, patients at risk of developing some liver diseases, e.g., people infected with hepatitis viruses,
patients with liver cirrhosis, or those suffering from alcoholism, might be candidates in whom ion channel
expression can be studied. Nevertheless, an important issue to solve is how to detect ion channel expression
in not easily accessible tissues such as the liver. An option may be ion channel detection by imaging studies.
For instance, Eag1 channel expression has been detected in vivo with labeled antibodies and near-infrared
imaging techniques, even in non-palpable tumors, in mice [143] . Another option may be the detection of ion
channels in extracellular vesicles released to the bloodstream by the liver. The investigation of ion channel
expression in extracellular vesicles released by the liver in different pathological conditions is needed. These
approaches should benefit patients by being diagnosed at earlier stages of the disease.

The precise molecular mechanisms involved in the association of ion channel function with cancer remain
elusive. The antiproliferative effect of channel blockage on cell proliferation indicates that ion flux may
play an important role. However, non-canonical functions of ion channel may also play a role, as occurs in
other tissues and diseases [144] . For instance, mutant non-conducting Kv10.1 potassium channels partially
preserve their oncogenic potential [145] . On the other hand, cleavage and translocation to the nucleus of a
fragment of the carboxy-terminus of some calcium channels induce the transcription of genes associated
with proliferation [146] . Thus, the potential role of non-canonical functions of ion channels in liver diseases
warrants investigation.

In accordance with the potential role of ion channels in liver diseases, blockage of over-expressed ion
channels or activation of downregulated channels results in the inhibition of hepatitis virus replication,
development of NAFLD, NASH, liver cirrhosis, and/or HCC [Table 2].

However, because of the relevance of ion channels in normal physiology, targeting these proteins may
have non-desirable side-effects. In this direction, drug repurposing is a very good alternative to reduce
costs and time for approval, as well as unknown side effects. Actually, several drugs have been suggested
for repurposing in cancer, including anti-histamines such as astemizole (which also blocks potassium
channels) and loratadine, as well as calcium and potassium channel blockers such as mibefradil and
glibenclamide, respectively [147,148] .