Tetrandrine, a novel inhibitor of ether‐à‐go‐go‐1 (Eag1), targeted to cervical cancer development

Abstract

Mortality-to-incidence ratios in patients with cancer are extremely high, positioning cancer as a major cause of death worldwide. Ether-à-go-go-1 (Eag1) is an ion channel that plays important roles in tumour proliferation, malignant transformation, invasion, metastasis, recurrence, and prognosis. Therefore, identifying potent and specific Eag1 channel inhibitors is crucial. In this study, we identified the first natural inhibitor of Eag1, the traditional Chinese medicine agent tetrandrine, and explored the underlying mechanism. Tetrandrine directly interacted with Eag1 and inhibited the currents in a concentration-dependent manner (IC 50 of 69.97 ± 5.2 μM), and the amino acids Ile 550 , Thr 552 , and Gln 557 in the Eag1 C-linker domain were critical for tetrandrine's inhibitory effect. Moreover, tetrandrine reduced the proliferation of HeLa cells and Chinese hamster ovary (CHO) cells stably expressing Eag1 in a concentrationdependent manner. Finally, tetrandrine (30 mg/kg/day) inhibited tumor growth in mice, demonstrating a 64.21% inhibitory rate of HeLa cell-transplanted tumors. These results suggest that tetrandrine is a potent and selective Eag1 channel inhibitor, and could act as a leading compound in the development of therapies for Eag1 ion channel dysfunction-induced diseases.

Tetrandrine: a review of its anticancer potentials, clinical settings, pharmacokinetics and drug delivery systems

“…[ 137 ] Tetrandrine, at a low concentration of 5 μ m , also substantially inhibits the proliferation of cervical cancer HeLa cells by around 20% by suppressing the Eag1 channels. [ 138 ] Likewise, as another study shows, 30 µ m of tetrandrine significantly inhibits the proliferation of cervical cancer SiHa cells in a dose‐ and time‐dependent manner, with the number of cells decreasing considerably by more than 50%. [ 73 ] Results from these studies suggest that tetrandrine is a promising agent for the treatment of human cervical cancer.…”

“…[ 73 ] Another research using tetrandrine as a novel inhibitor of ether‐à‐go‐go‐1 (Eag1) at daily doses of 30 and 60 mg/kg for 30 days significantly inhibited tumour growth in Balb/c mice‐bearing xenograft‐induced tumours of human cervical cancer origin (HeLa cells) in a dose‐dependent manner, demonstrating a 64.21% inhibitory rate over HeLa cell‐transplanted tumours. [ 138 ]…”

Toward Hijacking Bioelectricity in Cancer to Develop New Bioelectronic Medicine

“…Although Eag1 is almost exclusively expressed in neural tissue, ectopic expression leads to uncontrolled proliferation. [ 132 ] Eag1 has a potential interest as an early marker of cervical, colon, and breast cancers, [ 133 ] and treatment with channel blockers imipramine, [ 134 ] astemizole, [ 135 ] and tetrandrine [ 136 ] have been shown to reduce tumor growth. [ 137 ] hERG1 channels are often aberrantly expressed in cancer cells, contributing to evasion of apoptosis, proliferation, angiogenesis, and metastasis.…”

Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment

“…The triple mutant Eag1 I550A/T552A/Q557A, Figure 10) in the C‐linker domain showed significantly less current inhibition than wild‐type channels, while the individual mutations I550A, T552A, or Q557A did not have a similar effect. Tetrandrine ( 21 ) specificity was also investigated on K V 7.1, K ir 2.1, and HERG channels at 100 µM, a concentration that inhibits Eag1almost completely, but only slightly HERG 131 . Tetrandrine ( 21 ) also inhibits voltage‐gated Ca 2+ channels, large‐conductance Ca 2+ ‐activated K + channels, two‐pore channels as well as intracellular Ca 2+ pumps 208,209 .…”

“…Tetrandrine ( 21) specificity was also investigated on K V 7.1, K ir 2.1, and HERG channels at 100 µM, a concentration that inhibits Eag1almost completely, but only slightly HERG. 131 Tetrandrine ( 21) also inhibits voltage-gated Ca 2+ channels, large-conductance Ca 2+ -activated K + channels, two-pore channels as well as intracellular Ca 2+…”