Abstract
One of the remarkable recent developments in cancer research is the emergence of so-called “cancer neuroscience” which falls into two parts. The first is intrinsic, relating to the fact that many cancers of nonneural origin (most apparently the wide-ranging carcinomas) acquire neuronal properties, especially en route to becoming metastatic.1,2 The second is extrinsic and comprises tumors’ innervation.2,3 Overall, both aspects promote cancer progression, and bioelectric signaling is one of the main connecting factors. 4
The intrinsic properties include voltage-gated ion channels, most commonly associated with “excitable” cells (nerves and muscles). In particular, de novo expression of functional voltage-gated Na+ channels (VGSCs) promotes (may even initiate) metastasis, the main cause of death from cancer. Where examined, VGSC expression has been found to be accompanied by downregulation of outward K+ currents. Such a combination would make metastatic cancer cells electrically excitable, the backbone of the cellular excitability (CELEX) model. 5 Indeed, strongly metastatic cancer cells have been shown to generate spontaneous, tetrodotoxin (TTX)-sensitive spikes in vitro and in vivo.5–7 There is also significant evidence showing that functional VGSC expression promotes invasiveness in vitro and metastasis in vivo. 5 The evidence for the involvement of voltage-gated K+ (Kv) channels is patchier due to their (i) enormous diversity and (ii) role in cancer being multifaceted and stage-dependent. 5 According to the CELEX model, a drug that would simultaneously block VGSCs (i.e., decrease INa) and open Kv channels (i.e., increase IK) would represent a promising antimetastatic agent (Fig. 1).
Schematic representation of the CELEX model. Basically, a CELEX drug is one that inhibits VGSC activity (INaP significantly more than INaT) while promoting the activity of K+ channels (IK). The latter may be a Kv. The combined effect is inhibition of invasiveness/metastasis. Adapted and redrawn from Hung et al. 8
Hung et al. recently demonstrated that eslicarbazepine (ESL) can exert exactly this combination of effects. 8 ESL is a third-generation antiseizure drug that is chemically related to carbamazepine. It is marketed in North America as Aptiom and in Europe as Zebinix or Exalief.
Hung et al. studied the electrophysiological effects of ESL acetate (1–300 μM) on the mHippoE-14 cell line model, which exhibits the characteristics of embryonic hippocampal neurons. 8 The VGSC in these cells was blocked completely by 1 μM TTX, implying that it belongs to the TTX-sensitive subgroup (possibly Nav1.1, Nav1.2, and Nav1.6). Both the transient and persistent (late) components of the VGSC currents (INaT and INaP) were inhibited by ESL. Importantly, however, there was an order of magnitude difference in the respective IC50s (61.2 vs. 6.8 μM, respectively). That is, INaP was more susceptible to blockage by ESL.
As regards Kv, the authors tested the effects of ESL on the M-current [IK(M)] generated by KCNQ2/3 channels. In contrast to the VGSC currents, IK(M) was potentiated by ESL with an IC50 of 7.9 μM. 8
In our earlier study, minoxidil proved anti-invasive on human breast cancer MDA-MB-231 cells in vitro. 9 This could be due to the simultaneous opening of K+ channels (the primary mode of action of minoxidil) and inhibition of VGSC activity, since minoxidil was found also to exert some inhibition of the VGSC (neonatal Nav1.5) in these cells. 9 Importantly, a combination of minoxidil with ranolazine (a VGSC/INaP inhibitor) proved highly effective in inhibiting invasiveness. 9 Interestingly, this synergy was created although minoxidil is mainly an opener of KATP (not Kv) channels. This would imply that the basic CELEX notion may be applicable to K+ channels generally, and it is the associated membrane potential (hyperpolarization) that may be the key intermediary.
Taken together, the evidence presented by Hung et al. supports ESL as satisfying the requirements for being a potential antimetastatic drug in line with the CELEX model. In fact, there is some preclinical evidence from a rat model of glioma that ESL can produce anticancer effects. 10 Thus, in vitro, ESL (<50 μM) inhibited proliferation (arresting cell cycle in the G2/M phase) and migration. In vivo, ESL also suppressed intracranial tumor growth. In another in vitro study, ESL was shown to inhibit Nav1.5 currents in human breast cancer MDA-MB-231 cells. 11 Activity of this VGSC is well-known to promote metastatic activity in breast cancer in vitro and in vivo.12,13 The concentrations of ESL used in these preclinical studies are comparable to what has been measured in human spinal fluid. 14 The proposition that ESL could serve as an antimetastatic drug is supported by other partial but independent evidence. First, ranolazine, a specific blocker of INaP, the VGSC-persistent current inhibited preferentially by ESL, has already been proposed as a potential antimetastatic drug. 15 Second, Kv openers by themselves have also been shown to produce anti-invasive effects.5,16
In conclusion, ESL meets the hypothetical requirements of the CELEX model and could be repurposed as an antimetastatic drug. Interestingly, it is possible that it is INaP that is responsible for the pro-metastatic role of the VGSC. 15 Since the IC50 of ESL for INaP (i) is significantly lower than that for INaT and (ii) is comparable to that for Kv, it may be possible to use ESL against cancer at doses lower than that currently used against seizures. If so, this would make clinical use of ESL even safer. Such a prospect would be welcome by cancer patients who strive for effective systemic treatments that are also nontoxic! ESL can be taken safely for several years and its side effects are manageable (https://www.drugs.com/sfx/eslicarbazepine-side-effects.html). It may not be a cure but will keep disease (seizures) under control. Such a scenario would also be desirable to achieve for cancer, that is, making it a chronic condition. Then, patients can live with their cancer, avoiding treatments like chemotherapy which in the long-term can make the cancer worse. 17