{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:07:27Z","timestamp":1762862847889,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2016,10,10]],"date-time":"2016-10-10T00:00:00Z","timestamp":1476057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N10-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V\/PI labeling and Western blot for apoptosis analysis were conducted. A pharmacophore approach was used for mapping TXA1 onto pharmacophores for autophagy induction. Autophagy analyses included transmission electron microscopy for visualization of autophagic structures, fluorescence microscopy for observation of monodansylcadaverine (MDC) staining, pattern of LC3 expression in the cells and acridine orange staining, and Western blot for autophagic proteins expression; (3) Results: TXA1 induced autophagy of melanoma cells at the GI50 concentration (3.6 \u03bcM) and apoptosis at twice that concentration. Following treatment with TXA1, autophagic structures were observed, together with the accumulation of autophagosomes and the formation of autophagolysosomes. An increase in LC3-II levels was also observed, which was reverted by 3-methyladenine (3-MA) (an early stage autophagy-inhibitor) but further increased by E-64d\/pepstatin (late-stage autophagy inhibitors). Finally, 3-MA also reverted the effect of TXA1 in cellular viability; (4) Conclusion: TXA1 decreases the viability of melanoma cells by modulation of autophagy and may, therefore, serve as a lead compound for the development of autophagy modulators with antitumor activity.<\/jats:p>","DOI":"10.3390\/molecules21101343","type":"journal-article","created":{"date-parts":[[2016,10,10]],"date-time":"2016-10-10T10:35:19Z","timestamp":1476095719000},"page":"1343","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Modulation of Autophagy by a Thioxanthone Decreases the Viability of Melanoma Cells"],"prefix":"10.3390","volume":"21","author":[{"given":"Raquel","family":"Lima","sequence":"first","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2014Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, FMUP\u2014Faculty of Medicine of the University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Diana","family":"Sousa","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2014Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto, Portugal"},{"name":"Laboratory of Microbiology, Department of Biological Sciences, FFUP\u2014Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"given":"Ana","family":"Paiva","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP\u2014Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"given":"Andreia","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP\u2014Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"given":"Jo\u00e3o","family":"Barbosa","sequence":"additional","affiliation":[{"name":"CESPU, Instituto de Investiga\u00e7\u00e3o e Forma\u00e7\u00e3o Avan\u00e7ada em Ci\u00eancias e Tecnologias da Sa\u00fade, IUCS\u2014Instituto Universit\u00e1rio de Ci\u00eancias da Sa\u00fade, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal"}]},{"given":"Madalena","family":"Pedro","sequence":"additional","affiliation":[{"name":"CESPU, Instituto de Investiga\u00e7\u00e3o e Forma\u00e7\u00e3o Avan\u00e7ada em Ci\u00eancias e Tecnologias da Sa\u00fade, IUCS\u2014Instituto Universit\u00e1rio de Ci\u00eancias da Sa\u00fade, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4676-1409","authenticated-orcid":false,"given":"Madalena","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP\u2014Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Avenida General Norton de Matos, S\/N, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP\u2014Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Avenida General Norton de Matos, S\/N, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7801-4643","authenticated-orcid":false,"given":"M.","family":"Vasconcelos","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2014Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto, Portugal"},{"name":"Laboratory of Microbiology, Department of Biological Sciences, FFUP\u2014Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2016,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4161\/cbt.11.2.14627","article-title":"Autophagy and cancer therapy","volume":"11","author":"Maycotte","year":"2011","journal-title":"Cancer Boil. 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