{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:45:57Z","timestamp":1760784357835,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,10,20]],"date-time":"2017-10-20T00:00:00Z","timestamp":1508457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.<\/jats:p>","DOI":"10.3390\/md15100320","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T04:32:19Z","timestamp":1508733139000},"page":"320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-9023","authenticated-orcid":false,"given":"Haruhiko","family":"Fuwa","sequence":"first","affiliation":[{"name":"Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mizuho","family":"Sato","sequence":"additional","affiliation":[{"name":"Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ccr.2008.05.005","article-title":"Tumor cell metabolism: Cancer\u2019s Achilles\u2019 heel","volume":"13","author":"Kroemer","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/cas.12085","article-title":"Cancer metabolism: Key players in metabolic reprogramming","volume":"104","author":"Soga","year":"2013","journal-title":"Cancer Sci."},{"key":"ref_3","first-page":"6201","article-title":"Remarkable tolerance of tumor cells to nutrient deprivation: Possible new biochemical target for cancer therapy","volume":"60","author":"Izuishi","year":"2000","journal-title":"Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1056\/NEJMra1205406","article-title":"Autophagy in human health and disease","volume":"368","author":"Choi","year":"2013","journal-title":"N. 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