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Reversing uL3-mediated chemoresistance through synergistic combination of 5-FU and G-quadruplex ligands.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Reversing uL3-mediated chemoresistance through synergistic combination of 5-FU and G-quadruplex ligands.
Συγγραφείς: Di Porzio A; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Pecoraro A; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Danisi C; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Persico C; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., D'Auria L; CEINGE-Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486 80131 Naples, Italy., Germoglio M; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via Pietro Castellino 111, 80131 Naples, Italy., Iaccarino N; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Feliciello I; Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples,Italy.; Department of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia., Giancola C; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Randazzo A; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Russo G; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy., Russo A; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
Πηγή: NAR cancer [NAR Cancer] 2025 Nov 28; Vol. 7 (4), pp. zcaf046. Date of Electronic Publication: 2025 Nov 28 (Print Publication: 2025).
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Oxford University Press Country of Publication: England NLM ID: 101769553 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-8674 (Electronic) Linking ISSN: 26328674 NLM ISO Abbreviation: NAR Cancer Subsets: MEDLINE
Imprint Name(s): Original Publication: Oxford : Oxford University Press, [2019]-
Ιατρικοί όροι (MeSH): Fluorouracil*/pharmacology , Fluorouracil*/administration & dosage , Drug Resistance, Neoplasm*/drug effects , Drug Resistance, Neoplasm*/genetics , G-Quadruplexes*/drug effects , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/pathology , Antineoplastic Combined Chemotherapy Protocols*/pharmacology , Ribosomal Proteins*/genetics , Ribosomal Proteins*/metabolism, Picolinic Acids/pharmacology ; Tumor Suppressor Protein p53/genetics ; Humans ; Animals ; Drug Synergism ; Ligands ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Chick Embryo ; Ribosomal Protein L3 ; Mice ; Aminoquinolines
Περίληψη: Chemoresistance represents a significant challenge in the chemotherapy of colorectal cancer (CRC), limiting the effectiveness. In this regard, gene expression heterogeneity plays a critical role, influencing cancer cell adaptability and survival under chemotherapy. Our previous data revealed that ribosomal protein uL3 positively correlates with both chemoresistance and poor prognosis in CRC patients. This study explores the combination of 5-fluorouracil (5-FU), the first-line treatment of CRC, with G-quadruplex (G4) ligands, which have recently emerged as promising candidates for cancer therapy, to overcome uL3-mediated chemoresistance. We found that resistant p53-deficient and uL3-silenced CRC cells showed increased levels of G4 structures compared to both sensitive p53-deficient and p53-proficient cells, thereby exhibiting vulnerability to the cytotoxic effects of two well-established G4 ligands, pyridostatin (PDS) and RHPS4. The combination of 5-FU with PDS or RHPS4 exhibited a synergistic effect, selectively targeting tumor cells. This approach enabled a >10-fold reduction in the 5-FU dose, improving treatment efficacy. The effectiveness of this combination was further validated in vivo using uL3-silenced CRC cell-derived xenografts in a chicken embryo model. Overall, our findings highlight a novel and promising combination strategy that targets chemoresistance in CRCs characterized by non-functional p53 and reduced levels of uL3.
(© The Author(s) 2025. Published by Oxford University Press.)
Competing Interests: None declared.
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Substance Nomenclature: U3P01618RT (Fluorouracil)
0 (Ligands)
0 (pyridostatin)
0 (Picolinic Acids)
0 (RPL3 protein, human)
0 (Tumor Suppressor Protein p53)
0 (Ribosomal Proteins)
0 (Ribosomal Protein L3)
0 (Aminoquinolines)
Entry Date(s): Date Created: 20251201 Date Completed: 20251201 Latest Revision: 20260707
Update Code: 20260708
PubMed Central ID: PMC12661320
DOI: 10.1093/narcan/zcaf046
PMID: 41322077
Βάση Δεδομένων: MEDLINE
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  Data: Reversing uL3-mediated chemoresistance through synergistic combination of 5-FU and G-quadruplex ligands.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AU" term="%22Di+Porzio+A%22">Di Porzio A</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Pecoraro+A%22">Pecoraro A</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Danisi+C%22">Danisi C</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Persico+C%22">Persico C</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22D'Auria+L%22">D'Auria L</searchLink>; CEINGE-Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Germoglio+M%22">Germoglio M</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via Pietro Castellino 111, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Iaccarino+N%22">Iaccarino N</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Feliciello+I%22">Feliciello I</searchLink>; Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples,Italy.; Department of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia.<br /><searchLink fieldCode="AU" term="%22Giancola+C%22">Giancola C</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Randazzo+A%22">Randazzo A</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Russo+G%22">Russo G</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.<br /><searchLink fieldCode="AU" term="%22Russo+A%22">Russo A</searchLink>; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
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  Data: <searchLink fieldCode="JN" term="%22101769553%22">NAR cancer</searchLink> [NAR Cancer] 2025 Nov 28; Vol. 7 (4), pp. zcaf046. <i>Date of Electronic Publication: </i>2025 Nov 28 (<i>Print Publication: </i>2025).
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Oxford+University+Press%22">Oxford University Press </searchLink><i>Country of Publication: </i>England <i>NLM ID: </i>101769553 <i>Publication Model: </i>eCollection <i>Cited Medium: </i>Internet <i>ISSN: </i>2632-8674 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2226328674%22">26328674 </searchLink><i>NLM ISO Abbreviation: </i>NAR Cancer <i>Subsets: </i>MEDLINE
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  Data: <i>Original Publication</i>: Oxford : Oxford University Press, [2019]-
– Name: SubjectMESH
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  Data: <searchLink fieldCode="MM" term="%22Fluorouracil%22">Fluorouracil*</searchLink>/<searchLink fieldCode="MM" term="%22Fluorouracil+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Fluorouracil%22">Fluorouracil*</searchLink>/<searchLink fieldCode="MM" term="%22Fluorouracil+administration+%26+dosage%22">administration & dosage</searchLink> <br /><searchLink fieldCode="MM" term="%22Drug+Resistance%2C+Neoplasm%22">Drug Resistance, Neoplasm*</searchLink>/<searchLink fieldCode="MM" term="%22Drug+Resistance%2C+Neoplasm+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Drug+Resistance%2C+Neoplasm%22">Drug Resistance, Neoplasm*</searchLink>/<searchLink fieldCode="MM" term="%22Drug+Resistance%2C+Neoplasm+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22G-Quadruplexes%22">G-Quadruplexes*</searchLink>/<searchLink fieldCode="MM" term="%22G-Quadruplexes+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Colorectal+Neoplasms%22">Colorectal Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Colorectal+Neoplasms+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Colorectal+Neoplasms%22">Colorectal Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Colorectal+Neoplasms+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Colorectal+Neoplasms%22">Colorectal Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Colorectal+Neoplasms+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Antineoplastic+Combined+Chemotherapy+Protocols%22">Antineoplastic Combined Chemotherapy Protocols*</searchLink>/<searchLink fieldCode="MM" term="%22Antineoplastic+Combined+Chemotherapy+Protocols+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Ribosomal+Proteins%22">Ribosomal Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Ribosomal+Proteins+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Ribosomal+Proteins%22">Ribosomal Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Ribosomal+Proteins+metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Picolinic+Acids%22">Picolinic Acids</searchLink>/<searchLink fieldCode="MH" term="%22Picolinic+Acids+pharmacology%22">pharmacology</searchLink> ; <searchLink fieldCode="MH" term="%22Tumor+Suppressor+Protein+p53%22">Tumor Suppressor Protein p53</searchLink>/<searchLink fieldCode="MH" term="%22Tumor+Suppressor+Protein+p53+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Drug+Synergism%22">Drug Synergism</searchLink> ; <searchLink fieldCode="MH" term="%22Ligands%22">Ligands</searchLink> ; <searchLink fieldCode="MH" term="%22Xenograft+Model+Antitumor+Assays%22">Xenograft Model Antitumor Assays</searchLink> ; <searchLink fieldCode="MH" term="%22Cell+Line%2C+Tumor%22">Cell Line, Tumor</searchLink> ; <searchLink fieldCode="MH" term="%22Chick+Embryo%22">Chick Embryo</searchLink> ; <searchLink fieldCode="MH" term="%22Ribosomal+Protein+L3%22">Ribosomal Protein L3</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Aminoquinolines%22">Aminoquinolines</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Chemoresistance represents a significant challenge in the chemotherapy of colorectal cancer (CRC), limiting the effectiveness. In this regard, gene expression heterogeneity plays a critical role, influencing cancer cell adaptability and survival under chemotherapy. Our previous data revealed that ribosomal protein uL3 positively correlates with both chemoresistance and poor prognosis in CRC patients. This study explores the combination of 5-fluorouracil (5-FU), the first-line treatment of CRC, with G-quadruplex (G4) ligands, which have recently emerged as promising candidates for cancer therapy, to overcome uL3-mediated chemoresistance. We found that resistant p53-deficient and uL3-silenced CRC cells showed increased levels of G4 structures compared to both sensitive p53-deficient and p53-proficient cells, thereby exhibiting vulnerability to the cytotoxic effects of two well-established G4 ligands, pyridostatin (PDS) and RHPS4. The combination of 5-FU with PDS or RHPS4 exhibited a synergistic effect, selectively targeting tumor cells. This approach enabled a >10-fold reduction in the 5-FU dose, improving treatment efficacy. The effectiveness of this combination was further validated in vivo using uL3-silenced CRC cell-derived xenografts in a chicken embryo model. Overall, our findings highlight a novel and promising combination strategy that targets chemoresistance in CRCs characterized by non-functional p53 and reduced levels of uL3.<br /> (© The Author(s) 2025. Published by Oxford University Press.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: None declared.
– Name: Ref
  Label: References
  Group: RefInfo
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        Value: 10.1093/narcan/zcaf046
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        Text: English
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      – SubjectFull: Tumor Suppressor Protein p53 genetics
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      – SubjectFull: Ribosomal Protein L3
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      – SubjectFull: Mice
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      – SubjectFull: Aminoquinolines
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      – SubjectFull: Drug Resistance, Neoplasm drug effects
        Type: general
      – SubjectFull: Drug Resistance, Neoplasm genetics
        Type: general
      – SubjectFull: G-Quadruplexes drug effects
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      – SubjectFull: Colorectal Neoplasms drug therapy
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      – SubjectFull: Antineoplastic Combined Chemotherapy Protocols pharmacology
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      – SubjectFull: Ribosomal Proteins genetics
        Type: general
      – SubjectFull: Ribosomal Proteins metabolism
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    Titles:
      – TitleFull: Reversing uL3-mediated chemoresistance through synergistic combination of 5-FU and G-quadruplex ligands.
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              Text: 2025 Nov 28
              Type: published
              Y: 2025
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