PMID- 32585842
OWN - NLM
STAT- MEDLINE
DCOM- 20210322
LR  - 20210322
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 12
DP  - 2020 Jun 23
TI  - A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances 
      the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells.
LID - 10.3390/ijms21124452 [doi]
LID - 4452
AB  - 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-Gln(4)]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.
FAU - Marverti, Gaetano
AU  - Marverti G
AUID- ORCID: 0000-0002-9074-0795
AD  - Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, 
      University of Modena and Reggio Emilia, 41125 Modena, Italy.
FAU - Gozzi, Gaia
AU  - Gozzi G
AD  - Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, 
      University of Modena and Reggio Emilia, 41125 Modena, Italy.
FAU - Maretti, Eleonora
AU  - Maretti E
AUID- ORCID: 0000-0003-0048-2612
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Lauriola, Angela
AU  - Lauriola A
AD  - Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, 
      University of Modena and Reggio Emilia, 41125 Modena, Italy.
FAU - Severi, Leda
AU  - Severi L
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Sacchetti, Francesca
AU  - Sacchetti F
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Losi, Lorena
AU  - Losi L
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Pacifico, Salvatore
AU  - Pacifico S
AD  - Department of Chemical and Pharmaceutical Sciences, via Fossato di Mortara 17-19, 
      University of Ferrara, 44100 Ferrara, Italy.
FAU - Ferrari, Stefania
AU  - Ferrari S
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Ponterini, Glauco
AU  - Ponterini G
AUID- ORCID: 0000-0002-2115-0775
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Leo, Eliana
AU  - Leo E
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - Costi, Maria Paola
AU  - Costi MP
AUID- ORCID: 0000-0002-0443-5402
AD  - Department of Life Sciences, Via G. Campi 213/d, University of Modena and Reggio 
      Emilia, 41125 Modena, Italy.
FAU - D'Arca, Domenico
AU  - D'Arca D
AUID- ORCID: 0000-0002-7240-6005
AD  - Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, 
      University of Modena and Reggio Emilia, 41125 Modena, Italy.
LA  - eng
GR  - IG 10474/Associazione Italiana per la Ricerca sul Cancro/
GR  - IG 16977/Associazione Italiana per la Ricerca sul Cancro/
PT  - Journal Article
DEP - 20200623
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Liposomes)
RN  - 0 (Peptide Fragments)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - FCB9EGG971 (raltitrexed)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Apoptosis
MH  - Cell Proliferation
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Drug Therapy, Combination
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Fluorouracil/pharmacology
MH  - Humans
MH  - Liposomes/*chemistry
MH  - Ovarian Neoplasms/*drug therapy/metabolism/pathology
MH  - Peptide Fragments/*pharmacology
MH  - Polyethylene Glycols/chemistry
MH  - Quinazolines/pharmacology
MH  - Thiophenes/pharmacology
MH  - Thymidylate Synthase/*antagonists & inhibitors
MH  - Tumor Cells, Cultured
PMC - PMC7352236
OTO - NOTNLM
OT  - 5-fluorouracil
OT  - drug-resistance
OT  - human thymidylate synthase peptidic-inhibitors
OT  - ovarian cancer
OT  - pH-sensitive PEGylated liposomes
OT  - raltitrexed
COIS- The authors declare that there are no conflict of interest.
EDAT- 2020/06/27 06:00
MHDA- 2021/03/23 06:00
PMCR- 2020/06/01
CRDT- 2020/06/27 06:00
PHST- 2020/05/30 00:00 [received]
PHST- 2020/06/20 00:00 [revised]
PHST- 2020/06/20 00:00 [accepted]
PHST- 2020/06/27 06:00 [entrez]
PHST- 2020/06/27 06:00 [pubmed]
PHST- 2021/03/23 06:00 [medline]
PHST- 2020/06/01 00:00 [pmc-release]
AID - ijms21124452 [pii]
AID - ijms-21-04452 [pii]
AID - 10.3390/ijms21124452 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Jun 23;21(12):4452. doi: 10.3390/ijms21124452.