{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:52:15Z","timestamp":1787003535199,"version":"build-2736575974"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,5,16]],"date-time":"2019-05-16T00:00:00Z","timestamp":1557964800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,5,16]],"date-time":"2019-05-16T00:00:00Z","timestamp":1557964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81400935"],"award-info":[{"award-number":["81400935"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81472209"],"award-info":[{"award-number":["81472209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Science foundation of China"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Breast cancer is the most prevalent malignancy in women, which remains untreatable once metastatic. The treatment of advanced breast cancer is restricted due to chemotherapy resistance. We previously investigated anti-cancer potential of a tumor selective oncolytic adenovirus along with cisplatin in three lung cancer cells; A549, H292, and H661, and found it very efficient. To our surprise, this virotherapy showed remarkable cytotoxicity to chemo-resistant cancer cells. Here, we extended our investigation by using two breast cancer cells and their resistant sublines to further validate CRAd\u2019s anti-resistance properties. Results of\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    analyses recapitulated the similar anti-tumor potential of CRAd. Based on the molecular analysis through qPCR and western blotting, we suggest upregulation of coxsackievirus-adenovirus receptor (CAR) as a selective vulnerability of chemotherapy-resistant tumors. CAR knockdown and overexpression experiments established its important involvement in the success of CRAd-induced tumor inhibition. Additionally, through transwell migration assay we demonstrate that CRAd might have anti-metastatic properties. Mechanistic analysis show that CRAd pre-treatment could reverse epithelial to mesenchymal transition in breast cancer cells, which needs further verification. These insights may prove to be a timely opportunity for the application of CRAd in recurrent drug-resistant cancers.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-43668-8","type":"journal-article","created":{"date-parts":[[2019,5,16]],"date-time":"2019-05-16T06:05:46Z","timestamp":1557986746000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A tumor targeting oncolytic adenovirus can improve therapeutic outcomes in chemotherapy resistant metastatic human breast carcinoma"],"prefix":"10.1038","volume":"9","author":[{"given":"Ali","family":"Sakhawat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahir","family":"Muhammad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aamir Ali","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuechai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,5,16]]},"reference":[{"key":"43668_CR1","doi-asserted-by":"crossref","unstructured":"Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer 127, 2893-2917 (2010).","DOI":"10.1002\/ijc.25516"},{"key":"43668_CR2","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1038\/nrc1123","volume":"3","author":"R Agarwal","year":"2003","unstructured":"Agarwal, R. & Kaye, S. B. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nature Reviews Cancer 3, 502 (2003).","journal-title":"Nature Reviews Cancer"},{"key":"43668_CR3","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1016\/S0140-6736(13)62146-7","volume":"384","author":"GC Jayson","year":"2014","unstructured":"Jayson, G. C., Kohn, E. C., Kitchener, H. C. & Ledermann, J. A. Ovarian cancer. The Lancet 384, 1376\u20131388 (2014).","journal-title":"The Lancet"},{"key":"43668_CR4","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1158\/0008-5472.CAN-06-2574","volume":"67","author":"E Yag\u00fce","year":"2007","unstructured":"Yag\u00fce, E. et al. Ability to acquire drug resistance arises early during the tumorigenesis process. Cancer research 67, 1130\u20131137 (2007).","journal-title":"Cancer research"},{"key":"43668_CR5","doi-asserted-by":"crossref","unstructured":"Ushijima, K. Treatment for recurrent ovarian cancer\u2014at first relapse. Journal of oncology 2010 (2010).","DOI":"10.1155\/2010\/497429"},{"key":"43668_CR6","doi-asserted-by":"publisher","first-page":"17163","DOI":"10.1074\/jbc.M114.558288","volume":"289","author":"J Wang","year":"2014","unstructured":"Wang, J. & Wu, G. S. Role of autophagy in cisplatin resistance in ovarian cancer cells. Journal of Biological chemistry 289, 17163\u201317173 (2014).","journal-title":"Journal of Biological chemistry"},{"key":"43668_CR7","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1016\/S0959-8049(98)00227-5","volume":"34","author":"R Perez","year":"1998","unstructured":"Perez, R. Cellular and molecular determinants of cisplatin resistance. European Journal of Cancer 34, 1535\u20131542 (1998).","journal-title":"European Journal of Cancer"},{"key":"43668_CR8","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1517\/14740338.4.6.1051","volume":"4","author":"A Rossi","year":"2005","unstructured":"Rossi, A., Maione, P. & Gridelli, C. Safety profile of platinum-based chemotherapy in the treatment of advanced non-small cell lung cancer in elderly patients. Expert opinion on drug safety 4, 1051\u20131067 (2005).","journal-title":"Expert opinion on drug safety"},{"key":"43668_CR9","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.pharmthera.2016.02.008","volume":"160","author":"J Zhao","year":"2016","unstructured":"Zhao, J. Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacology & therapeutics 160, 145\u2013158 (2016).","journal-title":"Pharmacology & therapeutics"},{"key":"43668_CR10","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.drup.2016.07.001","volume":"28","author":"RH Wijdeven","year":"2016","unstructured":"Wijdeven, R. H., Pang, B., Assaraf, Y. G. & Neefjes, J. Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics. Drug Resistance Updates 28, 65\u201381 (2016).","journal-title":"Drug Resistance Updates"},{"key":"43668_CR11","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.canlet.2015.07.044","volume":"380","author":"Y Sun","year":"2016","unstructured":"Sun, Y. Tumor microenvironment and cancer therapy resistance. Cancer letters 380, 205\u2013215 (2016).","journal-title":"Cancer letters"},{"key":"43668_CR12","doi-asserted-by":"publisher","first-page":"308","DOI":"10.2174\/1567205010666131212110948","volume":"17","author":"D Fruci","year":"2016","unstructured":"Fruci, D. et al. Drug transporters and multiple drug resistance in the most common pediatric solid tumors. Current drug metabolism 17, 308\u2013316 (2016).","journal-title":"Current drug metabolism"},{"key":"43668_CR13","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.drup.2016.05.001","volume":"27","author":"W Li","year":"2016","unstructured":"Li, W. et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resistance Updates 27, 14\u201329 (2016).","journal-title":"Drug Resistance Updates"},{"key":"43668_CR14","doi-asserted-by":"publisher","first-page":"929","DOI":"10.4155\/fmc.15.36","volume":"7","author":"RJ Ferreira","year":"2015","unstructured":"Ferreira, R. J., Santos, D. J. D. & Ferreira, M.-J. U. P-glycoprotein and membrane roles in multidrug resistance. Future Medicinal Chemistry 7, 929\u2013946, https:\/\/doi.org\/10.4155\/fmc.15.36 (2015).","journal-title":"Future Medicinal Chemistry"},{"key":"43668_CR15","doi-asserted-by":"crossref","unstructured":"Sharom, F. J. ABC multidrug transporters: structure, function and role in chemoresistance (2008).","DOI":"10.2217\/14622416.9.1.105"},{"key":"43668_CR16","doi-asserted-by":"publisher","first-page":"7559","DOI":"10.1158\/0008-5472.CAN-07-0309","volume":"67","author":"C Perrotta","year":"2007","unstructured":"Perrotta, C. et al. Nitric oxide boosts chemoimmunotherapy via inhibition of acid sphingomyelinase in a mouse model of melanoma. Cancer research 67, 7559\u20137564 (2007).","journal-title":"Cancer research"},{"key":"43668_CR17","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3121\/cmr.4.3.218","volume":"4","author":"D Cross","year":"2006","unstructured":"Cross, D. & Burmester, J. K. Gene therapy for cancer treatment: past, present and future. Clinical medicine & research 4, 218\u2013227 (2006).","journal-title":"Clinical medicine & research"},{"key":"43668_CR18","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.molmed.2012.07.007","volume":"18","author":"R Cawood","year":"2012","unstructured":"Cawood, R. et al. Recombinant viral vaccines for cancer. Trends in molecular medicine 18, 564\u2013574 (2012).","journal-title":"Trends in molecular medicine"},{"key":"43668_CR19","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.addr.2006.05.005","volume":"58","author":"R Harrop","year":"2006","unstructured":"Harrop, R., John, J. & Carroll, M. W. Recombinant viral vectors: cancer vaccines. Advanced drug delivery reviews 58, 931\u2013947 (2006).","journal-title":"Advanced drug delivery reviews"},{"key":"43668_CR20","unstructured":"Moingeon, P. Recombinant cancer vaccines based on viral vectors. Developments in biologicals 116, 117\u2013122; discussion 133\u2013143 (2004)."},{"key":"43668_CR21","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1038\/78638","volume":"6","author":"FR Khuri","year":"2000","unstructured":"Khuri, F. R. et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nature medicine 6, 879 (2000).","journal-title":"Nature medicine"},{"key":"43668_CR22","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1111\/j.1349-7006.2002.tb02483.x","volume":"93","author":"K Asanuma","year":"2002","unstructured":"Asanuma, K. et al. A role for survivin in radioresistance of pancreatic cancer cells. Japanese Journal of Cancer Research 93, 1057\u20131062 (2002).","journal-title":"Japanese Journal of Cancer Research"},{"key":"43668_CR23","first-page":"271","volume":"92","author":"K Satoh","year":"2001","unstructured":"Satoh, K. et al. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer: Interdisciplinary International. Journal of the American Cancer Society 92, 271\u2013278 (2001).","journal-title":"Journal of the American Cancer Society"},{"key":"43668_CR24","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/sj.cgt.7700542","volume":"9","author":"TW Hermiston","year":"2002","unstructured":"Hermiston, T. W. & Kuhn, I. Armed therapeutic viruses: strategies and challenges to arming oncolytic viruses with therapeutic genes. Cancer gene therapy 9, 1022 (2002).","journal-title":"Cancer gene therapy"},{"key":"43668_CR25","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/sj.cr.7290191","volume":"13","author":"ZL Zhang","year":"2003","unstructured":"Zhang, Z. L. et al. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell research 13, 481 (2003).","journal-title":"Cell research"},{"key":"43668_CR26","doi-asserted-by":"publisher","first-page":"5224","DOI":"10.1158\/1078-0432.CCR-06-0244","volume":"12","author":"F Dong","year":"2006","unstructured":"Dong, F. et al. Eliminating Established Tumor in nu\/nu Nude Mice by a Tumor Necrosis Factor-\u03b1-Related Apoptosis-Inducing Ligand\u2013Armed Oncolytic Adenovirus. Clinical cancer research 12, 5224\u20135230 (2006).","journal-title":"Clinical cancer research"},{"key":"43668_CR27","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.7150\/jca.18371","volume":"8","author":"A Sakhawat","year":"2017","unstructured":"Sakhawat, A. et al. Upregulation of Coxsackie Adenovirus Receptor Sensitizes Cisplatin-Resistant Lung Cancer Cells to CRAd-Induced Inhibition. Journal of Cancer 8, 1425 (2017).","journal-title":"Journal of Cancer"},{"key":"43668_CR28","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.3390\/ijms20051125","volume":"20","author":"S Ali","year":"2019","unstructured":"Ali, S. et al. Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma. International Journal of Molecular Sciences 20, 1125 (2019).","journal-title":"International Journal of Molecular Sciences"},{"key":"43668_CR29","doi-asserted-by":"crossref","unstructured":"Yuuri H. et al. Biological Effects of Oncolytic Adenovirus on Epithelial-Mesenchymal Transition in Human Lung Cancer Cells. Molecular therapy 19, 800, h. d. o. S.- (2011).","DOI":"10.1016\/S1525-0016(16)37373-7"},{"key":"43668_CR30","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1158\/0008-5472.can-05-2328","volume":"66","author":"MD Lacher","year":"2006","unstructured":"Lacher, M. D. et al. Transforming Growth Factor-\u03b2 Receptor Inhibition Enhances Adenoviral Infectability of Carcinoma Cells via Up-Regulation of Coxsackie and Adenovirus Receptor in Conjunction with Reversal of Epithelial-Mesenchymal Transition. Cancer Research 66, 1648\u20131657, https:\/\/doi.org\/10.1158\/0008-5472.can-05-2328 (2006).","journal-title":"Cancer Research"},{"key":"43668_CR31","doi-asserted-by":"crossref","unstructured":"Tarver, T. Cancer facts & figures 2012 (ed. Taver, T.) 366\u2013367 (Taylor & Francis, 2012).","DOI":"10.1080\/15398285.2012.701177"},{"key":"43668_CR32","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nature10358","volume":"477","author":"CJ Breitbach","year":"2011","unstructured":"Breitbach, C. J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99 (2011).","journal-title":"Nature"},{"key":"43668_CR33","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/nbt.2287","volume":"30","author":"SJ Russell","year":"2012","unstructured":"Russell, S. J., Peng, K.-W. & Bell, J. C. Oncolytic virotherapy. Nature biotechnology 30, 658 (2012).","journal-title":"Nature biotechnology"},{"key":"43668_CR34","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1083\/jcb.200601018","volume":"172","author":"JM Lee","year":"2006","unstructured":"Lee, J. M., Dedhar, S., Kalluri, R. & Thompson, E. W. The epithelial\u2013mesenchymal transition: new insights in signaling, development, and disease. J Cell biol 172, 973\u2013981 (2006).","journal-title":"J Cell biol"},{"key":"43668_CR35","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical biochemistry 72, 248\u2013254 (1976).","journal-title":"Analytical biochemistry"},{"key":"43668_CR36","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.7314\/APJCP.2014.15.4.1639","volume":"15","author":"M Louisa","year":"2014","unstructured":"Louisa, M., Soediro, T. M. & Suyatna, F. D. In vitro modulation of P-glycoprotein, MRP-1 and BCRP expression by mangiferin in doxorubicin-treated MCF-7 cells. Asian Pac J Cancer Prev 15, 1639\u20131642 (2014).","journal-title":"Asian Pac J Cancer Prev"},{"key":"43668_CR37","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1016\/j.biopha.2018.08.041","volume":"107","author":"H Lin","year":"2018","unstructured":"Lin, H. et al. KDM5c inhibits multidrug resistance of colon cancer cell line by down-regulating ABCC1. Biomedicine & Pharmacotherapy 107, 1205\u20131209 (2018).","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"43668_CR38","doi-asserted-by":"publisher","first-page":"2973","DOI":"10.1007\/s11095-015-1679-1","volume":"32","author":"A Bernd","year":"2015","unstructured":"Bernd, A. et al. Characterization of efflux transport proteins of the human choroid plexus papilloma cell line HIBCPP, a functional in vitro model of the blood-cerebrospinal fluid barrier. Pharmaceutical research 32, 2973\u20132982 (2015).","journal-title":"Pharmaceutical research"},{"key":"43668_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2016.01.010","volume":"294","author":"H Deng","year":"2016","unstructured":"Deng, H. et al. Protective effect of Ac-SDKP on alveolar epithelial cells through inhibition of EMT via TGF-\u03b21\/ROCK1 pathway in silicosis in rat. Toxicology and applied pharmacology 294, 1\u201310 (2016).","journal-title":"Toxicology and applied pharmacology"},{"key":"43668_CR40","doi-asserted-by":"publisher","first-page":"697","DOI":"10.3748\/wjg.15.697","volume":"15","author":"K Li","year":"2009","unstructured":"Li, K., He, W., Lin, N., Wang, X. & Fan, Q.-X. N-cadherin knock-down decreases invasiveness of esophageal squamous cell carcinoma in vitro. World Journal of Gastroenterology: WJG 15, 697 (2009).","journal-title":"World Journal of Gastroenterology: WJG"},{"key":"43668_CR41","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.colsurfb.2017.12.010","volume":"162","author":"X Li","year":"2018","unstructured":"Li, X. et al. Human lung epithelial cells A549 epithelial-mesenchymal transition induced by PVA\/Collagen nanofiber. Colloids and Surfaces B: Biointerfaces 162, 390\u2013397 (2018).","journal-title":"Colloids and Surfaces B: Biointerfaces"},{"key":"43668_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/1471-230X-12-160","volume":"12","author":"CH Sukowati","year":"2012","unstructured":"Sukowati, C. H. et al. Gene and functional up-regulation of the BCRP\/ABCG2 transporter in hepatocellular carcinoma. BMC gastroenterology 12, 160 (2012).","journal-title":"BMC gastroenterology"},{"key":"43668_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19325-x","volume":"8","author":"AK Nanayakkara","year":"2018","unstructured":"Nanayakkara, A. K. et al. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Scientific reports 8, 967 (2018).","journal-title":"Scientific reports"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43668-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43668-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43668-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T04:46:59Z","timestamp":1671252419000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43668-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,16]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["43668"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-43668-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,16]]},"assertion":[{"value":"21 December 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 April 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7504"}}