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

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 (hNa_v1.5). Tamoxifen does not differentiate between the adult and embryonic splice variants of hNa_v1.5, the latter being predominant in tumors. However, it effectively blocks hNa_v1.5 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.