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. 2025 Jul 31.
doi: 10.1002/2211-5463.70091. Online ahead of print.

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

Karl Josef Föhr  1   2 , Michael Fauler  3 , Thomas Zimmer  4 , Bettina Jungwirth  1 , Hubert Schrezenmeier  2   5 , David Alexander Christian Messerer  2   5
Affiliations
Free article

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

Karl Josef Föhr et al. FEBS Open Bio. .
Free article

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.

Keywords: breast cancer; patch clamp; selective estrogen receptor modulator; tamoxifen; tumor therapy; voltage‐gated sodium channel.

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References

    1. Sula A, Hollingworth D, Ng LCT, Larmore M, DeCaen PG and Wallace BA (2021) A tamoxifen receptor within a voltage‐gated sodium channel. Mol Cell 81, 1160–1169.
    1. Tan CK, Chow PK, Findlay M, Wong C and Machin D (2000) Use of tamoxifen in hepatocellular carcinoma: a review and paradigm shift. J Gastroenterol Hepatol 15, 725–729.
    1. Miller M, Schoenfield L, Abdel‐Rahman M and Cebulla CM (2021) Is uveal melanoma a hormonally sensitive cancer? A review of the impact of sex hormones and pregnancy on uveal melanoma. Ocul Oncol Pathol 7, 239–250.
    1. Mao J, Yuan J, Wang L, Zhang H, Jin X, Zhu J, Li H, Xu B and Chen L (2013) Tamoxifen inhibits migration of estrogen receptor‐negative hepatocellular carcinoma cells by blocking the swelling‐activated chloride current. J Cell Physiol 228, 991–1001.
    1. Allen MC, Newland C, Valverde MA and Hardy SP (1998) Inhibition of ligand‐gated cation‐selective channels by tamoxifen. Eur J Pharmacol 354, 261–269.

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