{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T12:08:54Z","timestamp":1784635734323,"version":"3.55.0"},"reference-count":20,"publisher":"S. Karger AG","issue":"2","license":[{"start":{"date-parts":[[2000,1,1]],"date-time":"2000-01-01T00:00:00Z","timestamp":946684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2000,1,1]],"date-time":"2000-01-01T00:00:00Z","timestamp":946684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology"],"published-print":{"date-parts":[[2000]]},"abstract":"Apoptosis appears to be implicated in the pathogenesis and therapeutic applications of cancer. In this study we investigated the induction of apoptosis by 4-aminopyridine (4-AP), a K<sup>+<\/sup> channel blocker, and its mechanism in HepG2 human hepatoblastoma cells. 4-AP reduced cell viability and induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. In addition, 4-AP induced a sustained increase in intracellular Ca<sup>2+<\/sup> concentration, which was completely inhibited by the extracellular Ca<sup>2+<\/sup> chelation with EGTA. 4-AP also induced Mn<sup>2+<\/sup> influx, indicating that the 4-AP-induced increased intracellular Ca<sup>2+<\/sup> levels were due to activation of Ca<sup>2+<\/sup> influx pathway. 4-AP also depolarized membrane potential that was measured by using di-O-C<sub>5<\/sub>(3), a voltage-sensitive fluorescent dye. 4-AP-induced Ca<sup>2+<\/sup> influx was significantly inhibited not by voltage-operative Ca<sup>2+<\/sup> channel blockers (nifedipine or verapamil), but by flufenamic acid (FA), a known nonselective cation channel blocker. Quantitative analysis of apoptosis by the flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca<sup>2+<\/sup> chelator, significantly inhibited the 4-AP-induced apoptosis. Taken together, these results suggest that the observed 4-AP-induced apoptosis in the HepG2 cells may result from Ca<sup>2+<\/sup> influx through the activation of voltage-sensitive Ca<sup>2+<\/sup>-permeable non-selective cation channels. These results further suggest that membrane potential change by modulation of K<sup>+<\/sup> channel activity may be involved in the mechanism of apoptosis in human hepatoma cells.<\/jats:p>","DOI":"10.1159\/000028350","type":"journal-article","created":{"date-parts":[[2003,4,15]],"date-time":"2003-04-15T13:07:10Z","timestamp":1050412030000},"page":"74-81","source":"Crossref","is-referenced-by-count":33,"title":["Ca<sup>2+<\/sup> Influx Mediates Apoptosis Induced by 4-Aminopyridine, a K<sup>+<\/sup> Channel Blocker, in HepG2 Human Hepatoblastoma Cells"],"prefix":"10.1159","volume":"60","author":[{"given":"Jung-Ae","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Shin","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Wha","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga-Hwa","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Hee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Soo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2000,2,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199809)176:3<456::AID-JCP2>3.3.CO;2-Z"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199811)177:2<197::AID-JCP1>3.3.CO;2-Q"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1136(199811)24:3<313::AID-GLIA5>3.3.CO;2-E"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1007\/s002329900066"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1007\/s002329900332"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1016\/0898-6568(91)90062-Y"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11703"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19970415)48:2<122::AID-JNR4>3.0.CO;2-E"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.60.1.533"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1126\/science.281.5381.1322"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(91)90205-T"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1038\/348334a0"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(90)80977-Q"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-75-9-1116"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199702)170:2<166::AID-JCP8>3.0.CO;2-M"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.35.1.129"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.42.26471"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(94)90391-3"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1038\/41913"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(87)80430-1"}],"container-title":["Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/28350","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/28350","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:15:39Z","timestamp":1745468139000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000028350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000]]},"references-count":20,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2000,2,1]]}},"URL":"https:\/\/doi.org\/10.1159\/000028350","archive":["Portico"],"relation":{},"ISSN":["0031-7012","1423-0313"],"issn-type":[{"value":"0031-7012","type":"print"},{"value":"1423-0313","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000]]}}}