{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T22:42:46Z","timestamp":1780440166768,"version":"3.54.1"},"reference-count":69,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T00:00:00Z","timestamp":1592870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 10474"],"award-info":[{"award-number":["IG 10474"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 16977"],"award-info":[{"award-number":["IG 16977"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and\/or 5-FU and\/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs.<\/jats:p>","DOI":"10.3390\/ijms21124452","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T06:11:02Z","timestamp":1592892662000},"page":"4452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9074-0795","authenticated-orcid":false,"given":"Gaetano","family":"Marverti","sequence":"first","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Gozzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0048-2612","authenticated-orcid":false,"given":"Eleonora","family":"Maretti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Lauriola","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leda","family":"Severi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Sacchetti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Losi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Pacifico","sequence":"additional","affiliation":[{"name":"Department of Chemical and Pharmaceutical Sciences, via Fossato di Mortara 17\u201319, University of Ferrara, 44100 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2115-0775","authenticated-orcid":false,"given":"Glauco","family":"Ponterini","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0443-5402","authenticated-orcid":false,"given":"Maria Paola","family":"Costi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Via G. Campi 213\/d, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7240-6005","authenticated-orcid":false,"given":"Domenico","family":"D\u2019Arca","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/nrc4019","article-title":"Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer","volume":"15","author":"Bowtell","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4597","DOI":"10.1016\/0006-2952(88)90325-5","article-title":"Enhanced DNA repair and resistance to cisplatin in human ovarian cancer","volume":"37","author":"Lai","year":"1988","journal-title":"Biochem. 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