{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:09Z","timestamp":1787028429177,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2020,7,5]],"date-time":"2020-07-05T00:00:00Z","timestamp":1593907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K09792"],"award-info":[{"award-number":["15K09792"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K09121"],"award-info":[{"award-number":["18K09121"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca2+ entry (VGCE) and caspase-3 activation. In the present study, we investigated the role of depolarization and VGCE in aspirin\u2019s anti-melanoma effect. Aspirin and to a lesser extent, salicylate (\u22652.5 mM) induced a rapid (within seconds) depolarization, while they caused comparable levels of depolarization with a lag of 2~4 h. Reactive oxygen species (ROS) generation also occurred in the two-time points, and antioxidants abolished the early ROS generation and depolarization. At the same concentrations, the two drugs induced apoptotic and necrotic cell death in a caspase-independent manner, and antioxidants and Ca2+ channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca2+ (Ca2+m) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Cav1.2 isoform of l-type Ca2+ channel, and knockdown of Cav1.2 abolished the decrease in Ca2+m. Our findings suggest that aspirin and salicylate induce Ca2+m remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation.<\/jats:p>","DOI":"10.3390\/ijms21134771","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T03:19:27Z","timestamp":1594005567000},"page":"4771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS\u2012Depolarization\u2012Voltage-Gated Ca2+ Entry"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3026-3878","authenticated-orcid":false,"given":"Itsuho","family":"Fujikawa","sequence":"first","affiliation":[{"name":"Department of Dermatology, Nihon University Hospital, Tokyo 101-830, Japan"},{"name":"Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Suzuki-Karasaki","sequence":"additional","affiliation":[{"name":"Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Suzuki-Karasaki","sequence":"additional","affiliation":[{"name":"Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toyoko","family":"Ochiai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Nihon University Hospital, Tokyo 101-830, Japan"},{"name":"Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Suzuki-Karasaki","sequence":"additional","affiliation":[{"name":"Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s11523-016-0443-8","article-title":"Dabrafenib plus Trametinib: A Review in Advanced Melanoma with a BRAF (V600) Mutation","volume":"11","author":"Dhillon","year":"2016","journal-title":"Target. 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