# Blocking the voltage‐gated sodium channel hNav1.5 as a novel pH‐dependent mechanism of action for tamoxifen

## TL;DR

Tamoxifen, a breast cancer drug, may work by blocking sodium channels in cancer cells, especially in acidic environments typical of tumors.

## Contribution

Tamoxifen selectively inhibits sodium channels under acidic tumor-like conditions, revealing a pH-dependent antitumor mechanism.

## Key findings

- Tamoxifen blocks hNav1.5 sodium channels in slow-inactivated and open states, which are common in cancer cells.
- Binding affinity of tamoxifen increases significantly at acidic pH (pH 6.0) compared to normal pH (pH 7.4).
- This pH-dependent blocking suggests tamoxifen may selectively target sodium channels in tumor environments.

## Abstract

Tamoxifen, a selective estrogen receptor modulator, is widely used in breast cancer treatment, but also affects estrogen receptor‐negative tumors, suggesting alternative mechanisms. Voltage‐gated sodium channels (VGSCs) are implicated in metastasis, making them potential therapeutic targets. However, broad VGSC inhibition is impractical due to their essential physiological roles. Ideally, blockers should selectively target tumor‐associated VGSC properties while sparing normal cells. Since tamoxifen exhibits sodium channel‐blocking activity, we investigated its effects on tumor‐specific VGSC parameters. Electrophysiological experiments using the patch‐clamp technique were conducted on heterologously expressed human cardiac sodium channels (hNav1.5). Tamoxifen does not differentiate between the adult and embryonic splice variants of hNav1.5, the latter being predominant in tumors. However, it effectively blocks hNav1.5 in gating states (slow‐inactivated and open) assumed to be prevalent in cancer cells. Binding affinity increases significantly under acidic conditions (pH 6.0 vs. 7.4), mimicking the tumor microenvironment. The affinity for the slow‐inactivated state was 0.87 ± 0.16 μm at pH 7.4 and 0.16 ± 0.02 μm at pH 6.0. For the open state, half‐maximal inhibition occurred at 2.13 ± 0.08 μm and 0.57 ± 0.02 μm, respectively. Tamoxifen preferentially binds VGSCs under conditions characteristic of cancer tissue, particularly at acidic pH, suggesting its potential as a selective tumor‐targeting agent.

Patch‐clamp recordings revealed that tamoxifen inhibits voltage‐gated sodium channels, especially under acidic conditions, both common in metastatic cancer cells. These effects may explain certain antitumor properties of tamoxifen, highlighting a novel mechanism of action beyond its known endocrine effects.