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Article ; Online: Modeling Myotonic Dystrophy Type 2 Using

Marzullo, Marta / Coni, Sonia / De Simone, Assia / Canettieri, Gianluca / Ciapponi, Laura

International journal of molecular sciences

2023 Volume 24, Issue 18

Abstract: Myotonic dystrophy 2 (DM2) is a genetic multi-systemic disease primarily affecting skeletal muscle. It is caused by CCTGn expansion in intron 1 of ... ...

Abstract	Myotonic dystrophy 2 (DM2) is a genetic multi-systemic disease primarily affecting skeletal muscle. It is caused by CCTGn expansion in intron 1 of the
MeSH term(s)	Animals ; Drosophila melanogaster/genetics ; Myotonic Dystrophy/genetics ; Drosophila ; Introns/genetics ; Muscle, Skeletal ; RNA-Binding Proteins ; Drosophila Proteins/genetics
Chemical Substances	CNBP protein, Drosophila ; RNA-Binding Proteins ; Drosophila Proteins
Language	English
Publishing date	2023-09-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241814182
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Article: The Mechanism of Action of Biguanides: New Answers to a Complex Question.

Di Magno, Laura / Di Pastena, Fiorella / Bordone, Rosa / Coni, Sonia / Canettieri, Gianluca

Cancers

2022 Volume 14, Issue 13

Abstract: Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that ...

Abstract	Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this "complex" model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.
Language	English
Publishing date	2022-06-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14133220
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Article ; Online: Translating Hedgehog in Cancer: Controlling Protein Synthesis.

D'Amico, Davide / Canettieri, Gianluca

Trends in molecular medicine

2016 Volume 22, Issue 10, Page(s) 851–862

Abstract: Developmental Hedgehog (Hh) signaling is found deregulated in a broad spectrum of human malignancies and, thus, is an attractive target for cancer therapy. Currently available Hh inhibitors have shown the rapid occurrence of drug resistance, due to ... ...

Abstract	Developmental Hedgehog (Hh) signaling is found deregulated in a broad spectrum of human malignancies and, thus, is an attractive target for cancer therapy. Currently available Hh inhibitors have shown the rapid occurrence of drug resistance, due to altered signaling in collateral pathways. Emerging observations suggest that Hh signaling regulates protein translation in pathways that depend both on Cap- and IRES-mediated translation. In addition, translational regulators have been shown to modulate Hh function. In this opinion, we describe this novel Hh/translation crosstalk and argue that it plays a relevant role in Hh-mediated tumorigenesis and drug resistance. As such, we suggest that drugs targeting translation might be introduced in novel protocols aimed at treating malignancies driven by aberrant Hh signaling.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Drug Discovery/methods ; Hedgehog Proteins/antagonists & inhibitors ; Hedgehog Proteins/metabolism ; Humans ; Internal Ribosome Entry Sites/drug effects ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Protein Biosynthesis/drug effects ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; Signal Transduction/drug effects
Chemical Substances	Antineoplastic Agents ; Hedgehog Proteins ; Internal Ribosome Entry Sites ; RNA, Messenger
Language	English
Publishing date	2016-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2016.08.003
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Article ; Online: Thiol functionalised gold nanoparticles loaded with methotrexate for cancer treatment: From synthesis to in vitro studies on neuroblastoma cell lines

Salamone, Tommaso A. / Rutigliano, Lavinia / Pennacchi, Beatrice / Cerra, Sara / Matassa, Roberto / Nottola, Stefania / Sciubba, Fabio / Battocchio, Chiara / Marsotto, Martina / Del Giudice, Alessandra / Chumakov, Andrei / Davydok, Anton / Grigorian, Souren / Canettieri, Gianluca / Agostinelli, Enzo / Fratoddi, Ilaria

Journal of Colloid And Interface Science. 2023 Nov., v. 649 p.264-278

2023

Abstract: Colloidal gold nanoparticles (AuNPs) functionalised with hydrophilic thiols can be used as drug delivery probes, thanks to their small size and hydrophilic character. AuNPs possess unique properties for their use in nanomedicine, especially in cancer ... ...

Abstract	Colloidal gold nanoparticles (AuNPs) functionalised with hydrophilic thiols can be used as drug delivery probes, thanks to their small size and hydrophilic character. AuNPs possess unique properties for their use in nanomedicine, especially in cancer treatment, as diagnostics and therapeutic tools. Thiol functionalised AuNPs were synthesised and loaded with methotrexate (MTX). Spectroscopic and morphostructural characterisations evidenced the stability of the colloids upon interaction with MTX. Solid state (GISAXS, GIWAXS, FESEM, TEM, FTIR-ATR, XPS) and dispersed phase (UV–Vis, DLS, ζ-potential, NMR, SAXS) experiments allowed to understand structure-properties correlations. The nanoconjugate was tested in vitro (MTT assays) against two neuroblastoma cell lines: SNJKP and IMR5 with overexpressed n-Myc. Molar drug encapsulation efficiency was optimised to be >70%. A non-covalent interaction between the π system and the carboxylate moiety belonging to MTX and the charged aminic group of one of the thiols was found. The MTX loading slightly decreased the structural order of the system and increased the distance between the AuNPs. Free AuNPs showed no cytotoxicity whereas the AuNPs-MTX nanoconjugate had a more potent effect when compared to free MTX. The active role of AuNPs was evidenced by permeation studies: an improvement on penetration of the drug inside cells was evidenced.
Keywords	cancer therapy ; cytotoxicity ; diagnostic techniques ; encapsulation ; hydrophilicity ; methotrexate ; moieties ; nanogold ; nanomedicine ; permeability ; spectroscopy ; thiols ; Thiol functionalised gold nanoparticles ; Colloidal nanocarrier ; Drug delivery ; Non-covalent interaction ; SJNKP and IMR5 neuroblastoma cell lines ; 3MPS ; ATR ; AuNPs ; BBB ; DEA ; DF ; DHFR ; DLS ; DMEM-F12 ; DMSO ; EDP ; EDTA ; EPR ; FBS ; fcc ; FE-SEM ; FT-IR ; FWHM ; H2Oup ; HEPES ; IC50 ; L% ; LSPR ; MTT ; MTX ; MWCO ; NB ; NMR ; P% ; PBS ; RES ; RPMI 1640 Medium ; SAED ; SAXS ; SDD ; GISAXS ; GIWAXS ; TEM ; UHV ; XPS ; η%
Language	English
Dates of publication	2023-11
Size	p. 264-278.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	241597-5
ISSN	1095-7103 ; 0021-9797
ISSN (online)	1095-7103
ISSN	0021-9797
DOI	10.1016/j.jcis.2023.06.078
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Article: Partial Truncation of the C-Terminal Domain of PTCH1 in Cancer Enhances Autophagy and Metabolic Adaptability.

Caballero-Ruiz, Begoña / Gkotsi, Danai S / Ollerton, Hattie / Morales-Alcala, Cintli C / Bordone, Rosa / Jenkins, Georgia M L / Di Magno, Laura / Canettieri, Gianluca / Riobo-Del Galdo, Natalia A

Cancers

2023 Volume 15, Issue 2

Abstract: The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor's activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli pathway, its C-terminal domain (CTD) was reported to have ...

Abstract	The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor's activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli pathway, its C-terminal domain (CTD) was reported to have additional non-canonical functions. One of them is the reduction of autophagic flux through direct interaction with the Unc-51, like the autophagy activating kinase (ULK) complex subunit autophagy-related protein-101 (ATG101). With the aim of investigating whether this function of PTCH1 is important in cancer cell fitness, we first identified frameshift mutations in the CTD of PTCH1 in cancer databases. We demonstrated that those mutations disrupt PTCH1 interaction with ATG101 and increase autophagic flux. Using deletion mutants of the PTCH1 CTD in co-immunoprecipitation studies, we established that the 1309-1447 region is necessary and sufficient for interaction with ATG101. We next showed that the three most common PTCH1 CTD mutations in endometrial, stomach and colon adenocarcinomas that cause frameshifts at S1203, R1308 and Y1316 lack the ability to interact with ATG101 and limit autophagic flux, determined by bafilomycin A1-sensitive accumulation of the autophagy markers LC3BII and p62. We next engineered PTCH1 indel mutations at S1223 by CRISPR/Cas9 in SW620 colon cancer cells. Comparison of two independent clones harbouring PTCH1 S1223fs mutations to their isogenic parental cell lines expressing wild-type PTCH1 showed a significant increase in basal and rapamycin-stimulated autophagic flux, as predicted by loss of ATG101 interaction. Furthermore, the PTCH1 CTD mutant cells displayed increased proliferation in the presence of rapamycin and reduced sensitivity to glycolysis inhibitors. Our findings suggest that loss of the PTCH1-ATG101 interaction by mutations in the CTD of PTCH1 in cancer might confer a selective advantage by stimulating autophagy and facilitating adaptation to nutrient deprivation conditions.
Language	English
Publishing date	2023-01-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15020369
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Article ; Online: Nanotechnology-Based Strategies to Develop New Anticancer Therapies.

Magro, Massimiliano / Venerando, Andrea / Macone, Alberto / Canettieri, Gianluca / Agostinelli, Enzo / Vianello, Fabio

Biomolecules

2020 Volume 10, Issue 5

Abstract: The blooming of nanotechnology has made available a limitless landscape of solutions responding to crucial issues in many fields and, nowadays, a wide choice of nanotechnology-based strategies can be adopted to circumvent the limitations of conventional ... ...

Abstract	The blooming of nanotechnology has made available a limitless landscape of solutions responding to crucial issues in many fields and, nowadays, a wide choice of nanotechnology-based strategies can be adopted to circumvent the limitations of conventional therapies for cancer. Herein, the current stage of nanotechnological applications for cancer management is summarized encompassing the core nanomaterials as well as the available chemical-physical approaches for their surface functionalization and drug ligands as possible therapeutic agents. The use of nanomaterials as vehicles to delivery various therapeutic substances is reported emphasizing advantages, such as the high drug loading, the enhancement of the pay-load half-life and bioavailability. Particular attention was dedicated to highlight the importance of nanomaterial intrinsic features. Indeed, the ability of combining the properties of the transported drug with the ones of the nano-sized carrier can lead to multifunctional theranostic tools. In this view, fluorescence of carbon quantum dots, optical properties of gold nanoparticle and superparamagnetism of iron oxide nanoparticles, are fundamental examples. Furthermore, smart anticancer devices can be developed by conjugating enzymes to nanoparticles, as in the case of bovine serum amine oxidase (BSAO) and gold nanoparticles. The present review is aimed at providing an overall vision on nanotechnological strategies to face the threat of human cancer, comprising opportunities and challenges.
MeSH term(s)	Adsorption ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Biomedical Technology ; Humans ; Nanoparticles/chemistry ; Nanotechnology/methods
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2020-05-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom10050735
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Article: Polyamine Metabolism as a Therapeutic Target inHedgehog-Driven Basal Cell Carcinomaand Medulloblastoma.

Coni, Sonia / Di Magno, Laura / Serrao, Silvia Maria / Kanamori, Yuta / Agostinelli, Enzo / Canettieri, Gianluca

Cells

2019 Volume 8, Issue 2

Abstract: Hedgehog (Hh) signaling is a critical developmental regulator and its aberrant activation,due to somatic or germline mutations of genes encoding pathway components, causes Basal CellCarcinoma (BCC) and medulloblastoma (MB). A growing effort has been ... ...

Abstract	Hedgehog (Hh) signaling is a critical developmental regulator and its aberrant activation,due to somatic or germline mutations of genes encoding pathway components, causes Basal CellCarcinoma (BCC) and medulloblastoma (MB). A growing effort has been devoted at theidentification of druggable vulnerabilities of the Hedgehog signaling, leading to the identificationof various compounds with variable efficacy and/or safety. Emerging evidence shows that anaberrant polyamine metabolism is a hallmark of Hh-dependent tumors and that itspharmacological inhibition elicits relevant therapeutic effects in clinical or preclinical models ofBCC and MB. We discuss here the current knowledge of polyamine metabolism, its role in cancerand the available targeting strategies. We review the literature about the connection betweenpolyamines and the Hedgehog signaling, and the potential therapeutic benefit of targetingpolyamine metabolism in two malignancies where Hh pathways play a well-established role: BCCand MB.
MeSH term(s)	Animals ; Carcinogenesis/metabolism ; Carcinoma, Basal Cell/metabolism ; Carcinoma, Basal Cell/therapy ; Hedgehog Proteins/metabolism ; Humans ; Medulloblastoma/metabolism ; Medulloblastoma/therapy ; Molecular Targeted Therapy ; Polyamines/metabolism
Chemical Substances	Hedgehog Proteins ; Polyamines
Language	English
Publishing date	2019-02-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8020150
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Article ; Online: Thiol functionalised gold nanoparticles loaded with methotrexate for cancer treatment: From synthesis to in vitro studies on neuroblastoma cell lines.

Salamone, Tommaso A / Rutigliano, Lavinia / Pennacchi, Beatrice / Cerra, Sara / Matassa, Roberto / Nottola, Stefania / Sciubba, Fabio / Battocchio, Chiara / Marsotto, Martina / Del Giudice, Alessandra / Chumakov, Andrei / Davydok, Anton / Grigorian, Souren / Canettieri, Gianluca / Agostinelli, Enzo / Fratoddi, Ilaria

Journal of colloid and interface science

2023 Volume 649, Page(s) 264–278

Abstract: Hypothesis: Colloidal gold nanoparticles (AuNPs) functionalised with hydrophilic thiols can be used as drug delivery probes, thanks to their small size and hydrophilic character. AuNPs possess unique properties for their use in nanomedicine, especially ... ...

Abstract	Hypothesis: Colloidal gold nanoparticles (AuNPs) functionalised with hydrophilic thiols can be used as drug delivery probes, thanks to their small size and hydrophilic character. AuNPs possess unique properties for their use in nanomedicine, especially in cancer treatment, as diagnostics and therapeutic tools. Experiments: Thiol functionalised AuNPs were synthesised and loaded with methotrexate (MTX). Spectroscopic and morphostructural characterisations evidenced the stability of the colloids upon interaction with MTX. Solid state (GISAXS, GIWAXS, FESEM, TEM, FTIR-ATR, XPS) and dispersed phase (UV-Vis, DLS, ζ-potential, NMR, SAXS) experiments allowed to understand structure-properties correlations. The nanoconjugate was tested in vitro (MTT assays) against two neuroblastoma cell lines: SNJKP and IMR5 with overexpressed n-Myc. Findings: Molar drug encapsulation efficiency was optimised to be >70%. A non-covalent interaction between the π system and the carboxylate moiety belonging to MTX and the charged aminic group of one of the thiols was found. The MTX loading slightly decreased the structural order of the system and increased the distance between the AuNPs. Free AuNPs showed no cytotoxicity whereas the AuNPs-MTX nanoconjugate had a more potent effect when compared to free MTX. The active role of AuNPs was evidenced by permeation studies: an improvement on penetration of the drug inside cells was evidenced.
MeSH term(s)	Humans ; Methotrexate/chemistry ; Gold ; Nanoconjugates ; Sulfhydryl Compounds/chemistry ; Scattering, Small Angle ; Metal Nanoparticles/chemistry ; Drug Carriers/chemistry ; X-Ray Diffraction ; Neuroblastoma ; MCF-7 Cells
Chemical Substances	Methotrexate (YL5FZ2Y5U1) ; Gold (7440-57-5) ; Nanoconjugates ; Sulfhydryl Compounds ; Drug Carriers
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	241597-5
ISSN	1095-7103 ; 0021-9797
ISSN (online)	1095-7103
ISSN	0021-9797
DOI	10.1016/j.jcis.2023.06.078
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Article ; Online: Combined inhibition of polyamine metabolism and eIF5A hypusination suppresses colorectal cancer growth through a converging effect on MYC translation.

Coni, Sonia / Bordone, Rosa / Ivy, Devon Michael / Yurtsever, Zuleyha Nihan / Di Magno, Laura / D'Amico, Rodrigo / Cesaro, Bianca / Fatica, Alessandro / Belardinilli, Francesca / Bufalieri, Francesca / Maroder, Marella / De Smaele, Enrico / Di Marcotullio, Lucia / Giannini, Giuseppe / Agostinelli, Enzo / Canettieri, Gianluca

Cancer letters

2023 Volume 559, Page(s) 216120

Abstract: A key mechanism driving colorectal cancer (CRC) development is the upregulation of MYC and its targets, including ornithine decarboxylase (ODC), a master regulator of polyamine metabolism. Elevated polyamines promote tumorigenesis in part by activating ... ...

Abstract	A key mechanism driving colorectal cancer (CRC) development is the upregulation of MYC and its targets, including ornithine decarboxylase (ODC), a master regulator of polyamine metabolism. Elevated polyamines promote tumorigenesis in part by activating DHPS-mediated hypusination of the translation factor eIF5A, thereby inducing MYC biosynthesis. Thus, MYC, ODC and eIF5A orchestrate a positive feedback loop that represents an attractive therapeutic target for CRC therapy. Here we show that combined inhibition of ODC and eIF5A induces a synergistic antitumor response in CRC cells, leading to MYC suppression. We found that genes of the polyamine biosynthesis and hypusination pathways are significantly upregulated in colorectal cancer patients and that inhibition of ODC or DHPS alone limits CRC cell proliferation through a cytostatic mechanism, while combined ODC and DHPS/eIF5A blockade induces a synergistic inhibition, accompanied to apoptotic cell death in vitro and in mouse models of CRC and FAP. Mechanistically, we found that this dual treatment causes complete inhibition of MYC biosynthesis in a bimodal fashion, by preventing translational elongation and initiation. Together, these data illustrate a novel strategy for CRC treatment, based on the combined suppression of ODC and eIF5A, which holds promise for the treatment of CRC.
MeSH term(s)	Animals ; Mice ; Apoptosis ; Cell Proliferation ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Ornithine Decarboxylase/genetics ; Ornithine Decarboxylase/metabolism ; Ornithine Decarboxylase/pharmacology ; Polyamines/metabolism ; Humans ; Peptide Initiation Factors/genetics ; Peptide Initiation Factors/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Eukaryotic Translation Initiation Factor 5A
Chemical Substances	Ornithine Decarboxylase (EC 4.1.1.17) ; Polyamines ; Peptide Initiation Factors ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2023-03-08
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2023.216120
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Article ; Online: Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-β/Wnt3a Is Mediated by GLI2 Upregulation.

Wasson, Christopher W / Caballero-Ruiz, Begoña / Gillespie, Justin / Derrett-Smith, Emma / Mankouri, Jamel / Denton, Christopher P / Canettieri, Gianluca / Riobo-Del Galdo, Natalia A / Del Galdo, Francesco

Cells

2022 Volume 11, Issue 3

Abstract: Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 ... ...

Abstract	Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a and Hedgehog (Hh) signalling in fibrosis, we investigated their role in CLIC4 upregulation. Here, we show that TGF-β/SMAD3 co-operates with Wnt3a/β-catenin and Smoothened/GLI signalling to drive CLIC4 expression in normal dermal fibroblasts, and that the inhibition of β-catenin and GLI expression or activity abolishes TGF-β/SMAD3-dependent CLIC4 induction. We further show that the expression of the pro-fibrotic marker α-smooth muscle actin strongly correlates with CLIC4 expression in dermal fibroblasts. Further investigations revealed that the inhibition of CLIC4 reverses morphogen-dependent fibroblast activation. Our data highlights that CLIC4 is a common downstream target of TGF-β, Hh, and Wnt-3a through signalling crosstalk and we propose a potential therapeutic avenue using CLIC4 inhibitors.
MeSH term(s)	Chloride Channels/metabolism ; Fibroblasts/metabolism ; Fibrosis ; Hedgehog Proteins/metabolism ; Humans ; Nuclear Proteins/metabolism ; Transforming Growth Factor beta/metabolism ; Up-Regulation ; Wnt3A Protein/metabolism ; Zinc Finger Protein Gli2/metabolism ; beta Catenin/metabolism
Chemical Substances	CLIC4 protein, human ; Chloride Channels ; GLI2 protein, human ; Hedgehog Proteins ; Nuclear Proteins ; Transforming Growth Factor beta ; WNT3A protein, human ; Wnt3A Protein ; Zinc Finger Protein Gli2 ; beta Catenin
Language	English
Publishing date	2022-02-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11030530
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