{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:19:17Z","timestamp":1790104757510,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Italian Association for Cancer Research","doi-asserted-by":"publisher","award":["26313"],"award-info":[{"award-number":["26313"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"Italian Association for Cancer Research","doi-asserted-by":"publisher","award":["24590"],"award-info":[{"award-number":["24590"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>G-quadruplexes (G4s) are nucleic secondary structures characterized by G-tetrads. G4 motif stabilization induces DNA damage and cancer cell death; therefore, G4-targeting small molecules are the focus of clinical investigation. DNA destabilization induced by G4 ligands might potentiate the anticancer activity of agents targeting DNA or inhibiting its repair such as oncolytic viruses. This study represents the first approach combining G4 ligands, BRACO-19 (B19), pyridostatin (PDS), and the adenovirus dl922-947 in breast cancer cells. We demonstrated that G4 binders and dl922-947 induce cytotoxicity in breast cancer cells (MDA-MB-231 and MCF-7) and at higher doses in other neoplastic cell lines of thyroid (BHT-101 cells) and prostate (PC3 cells). G4 binders induce G4 motifs distributed in the S and G2\/M phases in MCF-7 cells. G4 binder\/dl922-947 combination increases cell cytotoxicity and the accumulation in subG0\/G1. Indeed, G4 binders favor viral entry and replication with no effect on coxsackie and adenovirus receptor. Notably, dl922-947 induces G4 motifs and its combination with PDS potentiates this effect in MCF-7 cells. The agents alone or in combination similarly enhanced cell senescence. Additionally, PDS\/dl922-947 combination inactivates STING signaling in MDA-MB-231 cells. Our results suggest that G4 binder\/virotherapy combination may represent a novel therapeutic anticancer approach.<\/jats:p>","DOI":"10.3390\/cells11162482","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:42:56Z","timestamp":1660124576000},"page":"2482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Combination of dl922-947 Oncolytic Adenovirus and G-Quadruplex Binders Uncovers Improved Antitumor Activity in Breast Cancer"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9242-6046","authenticated-orcid":false,"given":"Fabiana","family":"Napolitano","sequence":"first","affiliation":[{"name":"Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Di Somma","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Castellano","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-3544","authenticated-orcid":false,"given":"Jussara","family":"Amato","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7716-9010","authenticated-orcid":false,"given":"Bruno","family":"Pagano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Randazzo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8276-9769","authenticated-orcid":false,"given":"Giuseppe","family":"Portella","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6193-2835","authenticated-orcid":false,"given":"Anna Maria","family":"Malfitano","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1021\/acs.jmedchem.9b01866","article-title":"Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells","volume":"63","author":"Amato","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1002\/cmdc.201700749","article-title":"Targeting the BCL2 Gene Promoter G-Quadruplex with a New Class of Furopyridazinone-Based Molecules","volume":"13","author":"Amato","year":"2018","journal-title":"ChemMedChem"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5402","DOI":"10.1093\/nar\/gkl655","article-title":"Quadruplex DNA: Sequence, topology and structure","volume":"34","author":"Burge","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nrm.2017.3","article-title":"DNA G-quadruplexes in the human genome: Detection, functions and therapeutic potential","volume":"18","author":"Balasubramanian","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.bbrc.2020.03.178","article-title":"G-quadruplex in cancer biology and drug discovery","volume":"531","author":"Nakanishi","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ivancich, M., Schrank, Z., Wojdyla, L., Leviskas, B., Kuckovic, A., Sanjali, A., and Puri, N. (2017). Treating Cancer by Targeting Telomeres and Telomerase. Antioxidants, 6.","DOI":"10.3390\/antiox6010015"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Di Somma, S., Amato, J., Iaccarino, N., Pagano, B., Randazzo, A., Portella, G., and Malfitano, A.M. (2019). G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells. Cancers, 11.","DOI":"10.3390\/cancers11111797"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113986","DOI":"10.1016\/j.bcp.2020.113986","article-title":"Virotherapy: From single agents to combinatorial treatments","volume":"177","author":"Malfitano","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Malfitano, A.M., Pisanti, S., Napolitano, F., Di Somma, S., Martinelli, R., and Portella, G. (2020). Tumor-Associated Macrophage Status in Cancer Treatment. Cancers, 15.","DOI":"10.3390\/cancers12071987"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Di Somma, S., Napolitano, F., Portella, G., and Malfitano, A.M. (2021). Cross Talk of Macrophages with Tumor Microenvironment Cells and Modulation of Macrophages in Cancer by Virotherapy. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101309"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3389\/fonc.2019.00564","article-title":"The Oncolytic Virus dl922-947 Triggers Immunogenic Cell Death in Mesothelioma and Reduces Xenograft Growth","volume":"9","author":"Iannuzzi","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.18632\/oncotarget.6430","article-title":"The oncolytic virus dl922-947 reduces IL-8\/CXCL8 and MCP-1\/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma","volume":"7","author":"Passaro","year":"2016","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1089\/hum.2008.047","article-title":"Comparison of molecular strategies for breast cancer virotherapy using oncolytic adenovirus","volume":"19","author":"Carlisle","year":"2008","journal-title":"Hum. Gene Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"581","DOI":"10.2174\/138945009788680392","article-title":"The rb pathway and cancer therapeutics","volume":"10","author":"Du","year":"2009","journal-title":"Curr. Drug Targets"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1677\/ERC-10-0234","article-title":"AZD1152 negatively affects the growth of anaplastic thyroid carcinoma cells and enhances the effects of oncolytic virus dl922-947","volume":"18","author":"Libertini","year":"2011","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Iannuzzi, C.A., Indovina, P., Forte, I.M., Di Somma, S., Malfitano, A.M., Bruno, M., Portella, G., Pentimalli, F., and Giordano, A. (2020). Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197333"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.molonc.2014.07.022","article-title":"PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma","volume":"9","author":"Passaro","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1089\/hum.2011.120","article-title":"Inhibition of autophagy enhances the effects of E1A-defective oncolytic adenovirus dl922-947 against glioma cells in vitro and in vivo","volume":"23","author":"Botta","year":"2012","journal-title":"Hum. Gene Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6505","DOI":"10.1158\/1078-0432.CCR-08-0200","article-title":"Bevacizumab increases viral distribution in human anaplastic thyroid carcinoma xenografts and enhances the effects of E1A-defective adenovirus dl922-947","volume":"14","author":"Libertini","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1530\/ERC-13-0001","article-title":"Ionizing radiation enhances dl922-947-mediated cell death of anaplastic thyroid carcinoma cells","volume":"20","author":"Passaro","year":"2013","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nchembio.780","article-title":"Small-molecule-induced DNA damage identifies alternative DNA structures in human genes","volume":"8","author":"Rodriguez","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1089\/hum.2009.181","article-title":"PED\/PEA-15 modulates coxsackievirus-adenovirus receptor expression and adenoviral infectivity via ERK-mediated signals in glioma cells","volume":"21","author":"Botta","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/j.1476-5381.2010.01047.x","article-title":"Rimonabant reduces keratinocyte viability by induction of apoptosis and exerts topical anti-inflammatory activity in mice","volume":"162","author":"Malfitano","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Manna, S., Florio, D., Iacobucci, I., Napolitano, F., Benedictis, I., Malfitano, A.M., Monti, M., Ravera, M., Gabano, E., and Marasco, D. (2021). A Comparative Study of the Effects of Platinum (II) Complexes on \u03b2-Amyloid Aggregation: Potential Neurodrug Applications. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063015"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/mc.20666","article-title":"Involvement of Akt\/NF-\u03baB pathway in N6-isopentenyladenosine-induced apoptosis in human breast cancer cells","volume":"49","author":"Laezza","year":"2010","journal-title":"Mol. Carcinog."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/sj.bjp.0707651","article-title":"Rimonabant (SR141716) exerts anti-proliferative and immunomodulatory effects in human peripheral blood mononuclear cells","volume":"153","author":"Malfitano","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1096\/fj.13-238238","article-title":"Antiangiogenic effects of N6-isopentenyladenosine, an endogenous isoprenoid end product, mediated by AMPK activation","volume":"28","author":"Pisanti","year":"2014","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1189\/jlb.0413190","article-title":"N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation","volume":"94","author":"Ciaglia","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"De Magis, A., Kastl, M., Brossart, P., Heine, A., and Paeschke, K. (2021). BG-flow, a new flow cytometry tool for G-quadruplex quantification in fixed cells. BMC Biol., 19.","DOI":"10.1186\/s12915-021-00986-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s10238-005-0076-1","article-title":"The Coxsackie-adenovirus receptor has elevated expression in human breast cancer","volume":"5","author":"Martin","year":"2005","journal-title":"Clin. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41467-019-13689-y","article-title":"STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment","volume":"11","author":"Lohard","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41580-020-0236-x","article-title":"The regulation and functions of DNA and RNA G-quadruplexes","volume":"21","author":"Varshney","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.molmed.2020.05.002","article-title":"G-quadruplex, Friend or Foe: The Role of the G-quartet in Anticancer Strategies","volume":"26","author":"Carvalho","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1021\/acsomega.6b00044","article-title":"Folding Kinetics of Single Human Telomeric G-Quadruplex Affected by Cisplatin","volume":"1","author":"Ju","year":"2016","journal-title":"ACS Omega"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mach, N., Gao, J., Schaffarczyk, L., Janz, S., Ehrke-Schulz, E., Dittmar, T., Ehrhardt, A., and Zhang, W. (2020). Spectrum-Wide Exploration of Human Adenoviruses for Breast Cancer Therapy. Cancers, 12.","DOI":"10.3390\/cancers12061403"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1530\/ERC-10-0230","article-title":"Coxsackie and adenovirus receptor is a target and a mediator of estrogen action in breast cancer","volume":"18","author":"Vindrieux","year":"2011","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1093\/nar\/gkac090","article-title":"Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer","volume":"50","author":"Long","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/cas.14266","article-title":"Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer","volume":"111","author":"Loo","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6673","DOI":"10.1093\/nar\/gkab500","article-title":"G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells","volume":"49","author":"Miglietta","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41586-022-04847-2","article-title":"cGAS-STING drives the IL-6-dependent survival of chromosomally instable cancers","volume":"607","author":"Hong","year":"2022","journal-title":"Nature"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/16\/2482\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:06:52Z","timestamp":1760141212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/16\/2482"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":40,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cells11162482"],"URL":"https:\/\/doi.org\/10.3390\/cells11162482","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,10]]}}}