Ion Transport and Channel Regulation
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It is indicated that 3β-bufalin selectively suppresses cancer cell proliferation by coupling with receptor-type Na+,K+-ATPase to activate the VRAC in membrane microdomains rather than inhibiting Na+,K+-ATPase pump activity.
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Bufadienolides are toad-derived cardiotonic steroids with anti-cancer activity; however, their Na+,K+-ATPase-mediated anti-cancer mechanisms remain incompletely understood. Here, we compared the anti-proliferative effects of six bufadienolides, bufalin (3β-bufalin), resibufogenin, cinobufagin, telocinobufagin, cinobufotalin, and desacetylcinobufagin, on human colorectal cancer HT-29 cells. Among them, only 3β-bufalin significantly suppressed cell proliferation in a concentration-dependent manner, with an IC50 of 1.8 nM, whereas its hepatic metabolite, 3α-bufalin, showed markedly weaker activity, with an IC50 of 488 nM. 3β-Bufalin inhibited Na+,K+-ATPase activity with an IC50 of approximately 37 nM, indicating that it suppressed growth at concentrations lower than those required for pump inhibition. The Na+,K+-ATPase α1-isoform can function as a receptor-type (non-pumping) signaling platform linked to volume-regulated anion channel (VRAC) activation in membrane microdomains of cancer cells. 3β-Bufalin activated the VRAC with an EC50 of 4.6 nM, whereas 3α-bufalin and the other bufadienolides showed no detectable activation. The pharmacological inhibition of the VRAC and the disruption of cholesterol-rich membrane microdomains significantly attenuated the anti-proliferative effect of 3β-bufalin. Furthermore, 3β-bufalin induced G2/M cell cycle arrest, which was attenuated by VRAC inhibition. These findings indicate that 3β-bufalin selectively suppresses cancer cell proliferation by coupling with receptor-type Na+,K+-ATPase to activate the VRAC in membrane microdomains rather than inhibiting Na+,K+-ATPase pump activity.
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@article{Fujii2026Cardiac,
title = {Cardiac Glycoside 3β-Bufalin Suppresses Cancer Cell Proliferation by Coupling with Na+,K+-ATPase and Volume-Regulated Anion Channel Within Membrane Microdomains},
author = {Takuto Fujii and Takahiro Shimizu and Yasuharu Shimizu and Mizuki Katoh and Tomoyuki Okumura and Tsutomu Fujii and Hideki Sakai},
journal = {International Journal of Molecular Sciences},
year = {2026},
doi = {10.3390/ijms27177969},
url = {https://doi.org/10.3390/ijms27177969}
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