{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:11:08Z","timestamp":1787170268999,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T00:00:00Z","timestamp":1590624000000},"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>Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the potential antineoplastic activity of four newly synthesized olivacine derivatives. Multidrug resistance is a common phenomenon causing failure in the chemotherapy of many tumors. It is mainly related to increased function of P-glycoprotein, an efflux pump removing cytostatic out of the cells. The cell lines used in the study were colorectal carcinoma cell lines: LoVo (doxorubicin-sensitive) and LoVo\/DX (doxorubicin-resistant). The NHDF cell line was used to assess cell viability. First, the cells were incubated with olivacine derivatives. In the next step, the following assays were performed: DCF-DA assay, MTT assay, rhodamine 123 assay, detection of apoptosis, proliferation inhibition-mitotic index. The tested compounds showed higher antineoplastic potential and lower toxicity than the reference compound ellipticine. The results indicate that the new olivacine derivatives are good candidates for future anticancer drugs.<\/jats:p>","DOI":"10.3390\/molecules25112512","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T02:16:27Z","timestamp":1590718587000},"page":"2512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Antitumor Activity of New Olivacine Derivatives"],"prefix":"10.3390","volume":"25","author":[{"given":"Janusz","family":"Piasny","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1404-2274","authenticated-orcid":false,"given":"Benita","family":"Wiatrak","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1400-1819","authenticated-orcid":false,"given":"Agnieszka","family":"Dobosz","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2094-6533","authenticated-orcid":false,"given":"Beata","family":"Tyli\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8742-0790","authenticated-orcid":false,"given":"Tomasz","family":"G\u0119barowski","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,28]]},"reference":[{"key":"ref_1","first-page":"135","article-title":"Evaluation of individual sensitivity to cytostatic drugs of in vitro cultured lung tumor cells","volume":"33","author":"Zabel","year":"1999","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nrc1951","article-title":"The NCI60 human tumor cell line anticancer drug screen","volume":"6","author":"Shoemaker","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1021\/jo402593w","article-title":"Total synthesis of ellipticine quinones, olivacine, and calothrixin b","volume":"79","author":"Ramkumar","year":"2014","journal-title":"J. Org. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1016\/S0021-9258(18)52368-1","article-title":"DNA-drug recognition, and effects on topoisomerase II-mediated cytotoxicity. A three-mode binding model for ellipticine derivatives","volume":"66","author":"Monnot","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_5","first-page":"590","article-title":"Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives: Structure-activity relationship","volume":"42","author":"Fosse","year":"1992","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14998","DOI":"10.1074\/jbc.270.25.14998","article-title":"Topoisomerase II binds to ellipticine in the absence or presence of DNA: Chaeacterization of enzyme drug interactions by fluorescence spectroscopy","volume":"270","author":"Patchan","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4478","DOI":"10.1038\/sj.onc.1206777","article-title":"Rescue of mutant p53 transcription function by ellipticine","volume":"22","author":"Peng","year":"2003","journal-title":"Oncogene"},{"key":"ref_8","first-page":"3099","article-title":"Mutant p53 mediated induction of cell cycle arrest and apoptosis at G1 phase by 9-hydroxyellipticine","volume":"19","author":"Sugikawa","year":"1999","journal-title":"Anticancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Miller, C.M., O\u2019Sullivan, E.C., and McCarthy, F.O. (2019). Novel 11-substituted ellipticines as potent anticancer agents with divergent activity against cancer cells. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020090"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1097\/00001813-199710000-00001","article-title":"DNA topoisomerase targeting drugs: Mechanisms of action and perspectives","volume":"8","author":"Malonne","year":"1997","journal-title":"Anticancer. Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1124\/mol.53.2.213","article-title":"S16020-2, a new highly cytotoxic antitumor olivacine derivative: DNA interaction and DNA topoisomerase II inhibition","volume":"53","author":"Markovits","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1248\/cpb.50.1479","article-title":"1,5-Dimethyl-6H-pyridazino[4\u20135-b]carbazole, a 3-aza bioisoster of the antitumor alkaloid olivacine","volume":"50","author":"Haider","year":"2002","journal-title":"Chem. Pharm. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1124\/dmd.32.1.80","article-title":"The olivacine derivative S 16020 (9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-b) -carbazole-1-carboxamide) induces CYP1A and its own metabolism in human hepatocytes in primary culture","volume":"32","author":"Weaver","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","first-page":"823","article-title":"New pyridocarbazole derivatives. Synthesis and their in vitro anticancer activity","volume":"70","author":"Barowski","year":"2013","journal-title":"Acta Pol. Pharm.\u2014Drug Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21211","DOI":"10.18632\/oncotarget.25014","article-title":"Chemopreventive activity of celastrol in drug-resistant human colon carcinoma cell cultures","volume":"9","author":"Moreira","year":"2018","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1007\/s002800050845","article-title":"Circumvention of P-glycoprotein-mediated multidrug resistance by S16020\u20132: Kinetics of uptake and efflux in sensitive and resistant cell lines","volume":"42","author":"Atassi","year":"1998","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Juan, E., Le V\u00e9e, M., Mayati, A., Denizot, C., Parmentier, Y., and Fardel, O. (2016). Evaluation of P-glycoprotein inhibitory potential using a rhodamine 123 accumulation assay. Pharmaceutics, 8.","DOI":"10.3390\/pharmaceutics8020012"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.biopha.2017.01.053","article-title":"Anticancer activity of baicalein and luteolin studied in colorectal adenocarcinoma LoVo cells and drug-resistant LoVo\/Dx cells","volume":"88","author":"Uryga","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Purohit, V., Simeone, D.M., and Lyssiotis, C.A. (2019). Metabolic regulation of redox balance in cancer. Cancers (Basel), 11.","DOI":"10.3390\/cancers11070955"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Babu, K.R., and Tay, Y. (2019). The Yin-Yang regulation of reactive oxygen species and microRNAs in cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215335"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1155\/2019\/6793957","article-title":"Prooxidative Activity of Celastrol Induces Apoptosis, DNA Damage, and Cell Cycle Arrest in Drug-Resistant Human Colon Cancer Cells","volume":"2019","author":"Moreira","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/tpj.2009.49","article-title":"Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells","volume":"10","author":"Maiti","year":"2010","journal-title":"Pharmacogenom. J."},{"key":"ref_23","first-page":"78","article-title":"Molecular mechanisms of anthracyclines action","volume":"60","author":"Czyz","year":"2006","journal-title":"Post\u0119py Higieny Medycyny Do\u015bwiadczalnej (Online)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1096\/fj.02-0358fje","article-title":"Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species","volume":"17","author":"Wartenberg","year":"2003","journal-title":"FASEB J."},{"key":"ref_25","first-page":"1313","article-title":"Design, synthesis and analysis of anticancer activity of new SAR-based S16020 derivatives","volume":"75","author":"Tylinska","year":"2018","journal-title":"Acta Pol. Pharm.\u2014Drug Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10271","DOI":"10.1021\/bi00200a007","article-title":"High-field NMR and restrained molecular modeling studies on a DNA heteroduplex containing a modified apurinic abasic site in the form of covalently linked 9-aminoellipticine","volume":"33","author":"Singh","year":"1994","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4033","DOI":"10.1093\/nar\/20.15.4033","article-title":"Ellipticine increase the superhelical density of intracellular SV40 DNA by intercalation","volume":"20","author":"Chu","year":"1992","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7486","DOI":"10.1038\/sj.onc.1206949","article-title":"The role of p53 in chemosensitivity and radiosensitivity","volume":"22","year":"2003","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/sj.cdd.4401921","article-title":"Strategies for therapeutic targeting of the p53 pathway in cancer","volume":"13","author":"Wiman","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nm0302-282","article-title":"Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound","volume":"8","author":"Bykov","year":"2002","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Li, H., Zhang, J., Tong, J.H.M., Chan, A.W.H., Yu, J., Kang, W., and To, K.F. (2019). Targeting the oncogenic p53 mutants in colorectal cancer and other solid tumors. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20235999"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s43440-019-00004-1","article-title":"Effect of new olivacine derivatives on p53 protein level","volume":"72","author":"Wiatrak","year":"2020","journal-title":"Pharmacol. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/11\/2512\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:33:23Z","timestamp":1760175203000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/11\/2512"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,28]]},"references-count":32,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["molecules25112512"],"URL":"https:\/\/doi.org\/10.3390\/molecules25112512","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,28]]}}}