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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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 (3\u03b2-bufalin), resibufogenin, cinobufagin, telocinobufagin, cinobufotalin, and desacetylcinobufagin, on human colorectal cancer HT-29 cells. Among them, only 3\u03b2-bufalin significantly suppressed cell proliferation in a concentration-dependent manner, with an IC50 of 1.8 nM, whereas its hepatic metabolite, 3\u03b1-bufalin, showed markedly weaker activity, with an IC50 of 488 nM. 3\u03b2-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 \u03b11-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. 3\u03b2-Bufalin activated the VRAC with an EC50 of 4.6 nM, whereas 3\u03b1-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 3\u03b2-bufalin. Furthermore, 3\u03b2-bufalin induced G2\/M cell cycle arrest, which was attenuated by VRAC inhibition. These findings indicate that 3\u03b2-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.<\/jats:p>","DOI":"10.3390\/ijms27177969","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:53:28Z","timestamp":1788789208000},"page":"7969","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiac Glycoside 3\u03b2-Bufalin Suppresses Cancer Cell Proliferation by Coupling with Na+,K+-ATPase and Volume-Regulated Anion Channel Within Membrane Microdomains"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0547-1691","authenticated-orcid":false,"given":"Takuto","family":"Fujii","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-7828","authenticated-orcid":false,"given":"Takahiro","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yasuharu","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Tokyo Research Center, Kyushin Pharmaceutical Co., Ltd., Tokyo 166-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mizuki","family":"Katoh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Tomoyuki","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0625-1911","authenticated-orcid":false,"given":"Tsutomu","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9753-7941","authenticated-orcid":false,"given":"Hideki","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Qi, J., Zulfiker, A.H.M., Li, C., Good, D., and Wei, M.Q. 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