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September 8, 2026International Journal of Molecular SciencesOpen Access

3β-bufalin potently suppresses colorectal cancer cell proliferation by coupling with Na+,K+-ATPase to activate VRAC.

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Why the study?

Bufadienolides are toad-derived cardiotonic steroids with anti-cancer activity, but their Na+,K+-ATPase-mediated anti-cancer mechanisms remain incompletely understood.

Population

Human colorectal cancer HT-29 cells

Comparison

Six bufadienolides (bufalin, resibufogenin, cinobufagin, telocinobufagin, cinobufotalin, desacetylcinobufagin) and 3α-bufalin

Design

In vitro laboratory study

Key result

3β-bufalin selectively suppressed colorectal cancer cell proliferation (IC50 1.8 nM) by coupling with receptor-type Na+,K+-ATPase to activate VRAC in membrane microdomains.

Authors

TFTakuto FujiiTFTakuto FujiiTSTakahiro Shimizu

Discussion

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Overview

Should not yet change colorectal cancer practice; leaves open VRAC as a bufadienolide target for further study.

Key Points

  • To determine the molecular mechanisms by which toad-derived bufadienolides, particularly 3β-bufalin, suppress human colorectal cancer cell proliferation through Na⁺,K⁺-ATPase and membrane signaling domains.
  • Compared the anti-proliferative effects of six bufadienolides and the metabolite 3α-bufalin in human colorectal cancer HT-29 cells.
  • Measured Na⁺,K⁺-ATPase enzymatic inhibition and volume-regulated anion channel (VRAC) activation across compound concentrations.
  • Assessed G2/M cell cycle arrest alongside pharmacological inhibition of VRAC and disruption of cholesterol-rich membrane microdomains.
  • 3β-Bufalin selectively inhibited HT-29 cell proliferation with an IC50 of 1.8 nM, whereas 3α-bufalin had an IC50 of 488 nM and Na⁺,K⁺-ATPase pump inhibition occurred at an IC50 of approximately 37 nM.
  • 3β-Bufalin activated the VRAC with an EC50 of 4.6 nM, while 3α-bufalin and the other five bufadienolides produced no detectable VRAC activation.
  • 3β-Bufalin induced G2/M cell cycle arrest, which was significantly attenuated by both VRAC inhibition and membrane microdomain disruption.

Structured PICO

P
Population
Human colorectal cancer HT-29 cells
I
Intervention
3β-bufalin and other bufadienolides (resibufogenin, cinobufagin, telocinobufagin, cinobufotalin, desacetylcinobufagin, and 3α-bufalin)
O
Outcome
Cell proliferation suppressionsurrogate

Main Result

Effect estimate: IC50 1.8 nM

3β-bufalin suppresses cancer cell proliferation by coupling with receptor-type Na+,K+-ATPase to activate VRAC in membrane microdomains, rather than by inhibiting pump activity.

Cite This Study

Fujii et al. (2026) studied Colorectal cancer (in vitro HT-29 cells). 3β-bufalin vs. 3α-bufalin and other bufadienolides was evaluated on Cell proliferation (IC50 1.8 nM). 3β-bufalin selectively suppressed colorectal cancer cell proliferation (IC50 1.8 nM) by coupling with receptor-type Na+,K+-ATPase to activate VRAC in membrane microdomains.

synapsesocial.com/papers/6a9fd82058e84d0ff5b476b2https://doi.org/10.3390/ijms27177969
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