{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:20:01Z","timestamp":1775910001912,"version":"3.50.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2017YFC1601200"],"award-info":[{"award-number":["2017YFC1601200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To rapidly generate host cells with resistance to multiple compounds for differentiating drug action on parasite target or the host cell target (i.e. on-target or off-target effect) against the zoonotic enteric parasite Cryptosporidium parvum.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Transient overexpression of a multidrug resistance protein 1 (MDR1) gene in host cells (HCT-8 cell line) was explored to increase drug tolerance of the host cells to selected anti-cryptosporidial leads. In vitro cytotoxicity and anti-cryptosporidial efficacy of selected compounds were evaluated on the parasite grown in WT parental and transiently transfected HCT-8 cells. The approach was based on the theory that, for an epicellular parasite receiving consistent exposure to compounds in culture medium, overexpressing MDR1 in HCT-8 cells would increase drug tolerance of host cells to selected compounds but would not affect the anti-cryptosporidial efficacy if the compounds acted solely on the parasite target and the drug action on host cell target played no role on the antiparasitic efficacy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Six known anti-cryptosporidial leads were tested. Transient overexpression of MDR1 increased drug tolerance of HCT-8 cells on paclitaxel, doxorubicin HCl and vincristine sulphate (2.11- to 2.27-fold increase), but not on cyclosporin A, daunorubicin HCl and nitazoxanide. Increased drug tolerance in host cells had no effect on antiparasitic efficacy of paclitaxel, but affected that of doxorubicin HCl.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Data confirmed that, at efficacious concentrations, paclitaxel acted mainly on the parasite target, while doxorubicin might act on both parasite and host cell targets. This model can be employed for studying the action of additional anti-cryptosporidial leads, and adapted to studying drug action in other epicellular pathogens. The limitation of the model is that the anti-cryptosporidial leads\/hits need to be MDR1 substrates.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkab369","type":"journal-article","created":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T11:34:49Z","timestamp":1631878489000},"page":"124-134","source":"Crossref","is-referenced-by-count":10,"title":["Host cells with transient overexpression of <i>MDR1<\/i> as a novel <i>in vitro<\/i> model for evaluating on-target effect for activity against the epicellular <i>Cryptosporidium<\/i> parasite"],"prefix":"10.1093","volume":"77","author":[{"given":"Bo","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodong","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jigang","family":"Yin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0659","authenticated-orcid":false,"given":"Guan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"2022010520143747900_dkab369-B1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S1473-3099(14)70772-8","article-title":"A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium","volume":"15","author":"Checkley","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"2022010520143747900_dkab369-B2","doi-asserted-by":"crossref","first-page":"e758","DOI":"10.1016\/S2214-109X(18)30283-3","article-title":"Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study","volume":"6","author":"Khalil","year":"2018","journal-title":"Lancet Glob Health"},{"key":"2022010520143747900_dkab369-B3","doi-asserted-by":"crossref","first-page":"e12800","DOI":"10.1111\/pim.12800","article-title":"Development of an immunocompetent mouse model susceptible to Cryptosporidium tyzzeri infection","volume":"43","author":"Huang","year":"2021","journal-title":"Parasite Immunol"},{"key":"2022010520143747900_dkab369-B4","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2217\/fmb.09.115","article-title":"Challenges and prospects for a Cryptosporidium vaccine","volume":"5","author":"Mead","year":"2010","journal-title":"Future Microbiol"},{"key":"2022010520143747900_dkab369-B5","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.vetpar.2014.02.027","article-title":"Efficacy of halofuginone lactate against experimental cryptosporidiosis in goat neonates","volume":"202","author":"Petermann","year":"2014","journal-title":"Vet Parasitol"},{"key":"2022010520143747900_dkab369-B6","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1136\/vr.d1492","article-title":"Efficacy of halofuginone lactate in the prevention of cryptosporidiosis in dairy calves","volume":"168","author":"Trotz-Williams","year":"2011","journal-title":"Vet Rec"},{"key":"2022010520143747900_dkab369-B7","doi-asserted-by":"crossref","first-page":"e0004242","DOI":"10.1371\/journal.pntd.0004242","article-title":"Addressing Cryptosporidium infection among young children in low-income settings: the crucial role of new and existing drugs for reducing morbidity and mortality","volume":"10","author":"Shoultz","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"key":"2022010520143747900_dkab369-B8","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.3389\/fmicb.2019.01999","article-title":"Discovery of novel anti-cryptosporidial activities from natural products by in vitro high-throughput phenotypic screening","volume":"10","author":"Jin","year":"2019","journal-title":"Front Microbiol"},{"key":"2022010520143747900_dkab369-B9","doi-asserted-by":"crossref","first-page":"e1008600","DOI":"10.1371\/journal.ppat.1008600","article-title":"A symbiotic bacterium of shipworms produces a compound with broad spectrum anti-apicomplexan activity","volume":"16","author":"O'Connor","year":"2020","journal-title":"PLoS Pathog"},{"key":"2022010520143747900_dkab369-B10","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ijpddr.2020.08.006","article-title":"Novel acyl carbamates and acyl\/diacyl ureas show in vitro efficacy against Toxoplasma gondii and Cryptosporidium parvum","volume":"14","author":"Li","year":"2020","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"2022010520143747900_dkab369-B11","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1021\/acsinfecdis.0c00803","article-title":"Pyrrolopyrimidine bumped kinase inhibitors for the treatment of cryptosporidiosis","volume":"7","author":"Hulverson","year":"2021","journal-title":"ACS Infect Dis"},{"key":"2022010520143747900_dkab369-B12","doi-asserted-by":"crossref","first-page":"e1007953","DOI":"10.1371\/journal.ppat.1007953","article-title":"Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum","volume":"15","author":"Li","year":"2019","journal-title":"PLoS Pathog"},{"key":"2022010520143747900_dkab369-B13","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature22337","article-title":"A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis","volume":"546","author":"Manjunatha","year":"2017","journal-title":"Nature"},{"key":"2022010520143747900_dkab369-B14","doi-asserted-by":"crossref","first-page":"eaba8412","DOI":"10.1126\/scitranslmed.aba8412","article-title":"Bicyclic azetidines kill the diarrheal pathogen Cryptosporidium in mice by inhibiting parasite phenylalanyl-tRNA synthetase","volume":"12","author":"Vinayak","year":"2020","journal-title":"Sci Transl Med"},{"key":"2022010520143747900_dkab369-B15","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.taap.2004.10.012","article-title":"Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense","volume":"204","author":"Leslie","year":"2005","journal-title":"Toxicol Appl Pharmacol"},{"key":"2022010520143747900_dkab369-B16","doi-asserted-by":"crossref","first-page":"7735","DOI":"10.1073\/pnas.84.21.7735","article-title":"Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues","volume":"84","author":"Thiebaut","year":"1987","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022010520143747900_dkab369-B17","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev.pharmtox.39.1.361","article-title":"Biochemical, cellular, and pharmacological aspects of the multidrug transporter","volume":"39","author":"Ambudkar","year":"1999","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2022010520143747900_dkab369-B18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(02)00169-2","article-title":"Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview","volume":"55","author":"Schinkel","year":"2003","journal-title":"Adv Drug Deliv Rev"},{"key":"2022010520143747900_dkab369-B19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2014.11.013","article-title":"Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy","volume":"149","author":"Silva","year":"2015","journal-title":"Pharmacol Ther"},{"key":"2022010520143747900_dkab369-B20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.canlet.2015.10.010","article-title":"Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: a review of the past decade","volume":"370","author":"Chen","year":"2016","journal-title":"Cancer Lett"},{"key":"2022010520143747900_dkab369-B21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.acr.2014.10.001","article-title":"Apical ABC transporters and cancer chemotherapeutic drug disposition","volume":"125","author":"Durmus","year":"2015","journal-title":"Adv Cancer Res"},{"key":"2022010520143747900_dkab369-B22","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nrd3028","article-title":"Membrane transporters in drug development","volume":"9","author":"International Transporter","year":"2010","journal-title":"Nat Rev Drug Discov"},{"key":"2022010520143747900_dkab369-B23","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","article-title":"Revisiting the role of ABC transporters in multidrug-resistant cancer","volume":"18","author":"Robey","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"2022010520143747900_dkab369-B24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-4939-9748-0_4","article-title":"Cryptosporidium oocyst purification using discontinuous gradient centrifugation","volume":"2052","author":"Arrowood","year":"2020","journal-title":"Methods Mol Biol"},{"key":"2022010520143747900_dkab369-B25","doi-asserted-by":"crossref","first-page":"89S","DOI":"10.1111\/j.1550-7408.1996.tb05015.x","article-title":"Improved purification methods for calf-derived Cryptosporidium parvum oocysts using discontinuous sucrose and cesium chloride gradients","volume":"43","author":"Arrowood","year":"1996","journal-title":"J Eukaryot Microbiol"},{"key":"2022010520143747900_dkab369-B26","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12943-017-0593-z","article-title":"Targeting CD133 improves chemotherapeutic efficacy of recurrent pediatric pilocytic astrocytoma following prolonged chemotherapy","volume":"16","author":"Xi","year":"2017","journal-title":"Mol Cancer"},{"key":"2022010520143747900_dkab369-B27","doi-asserted-by":"crossref","first-page":"15819","DOI":"10.1073\/pnas.0901216106","article-title":"miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses","volume":"106","author":"Liu","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022010520143747900_dkab369-B28","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1093\/infdis\/jix689","article-title":"The existing drug vorinostat as a new lead against cryptosporidiosis by targeting the parasite histone deacetylases","volume":"217","author":"Guo","year":"2018","journal-title":"J Infect Dis"},{"key":"2022010520143747900_dkab369-B29","doi-asserted-by":"crossref","first-page":"991","DOI":"10.3389\/fmicb.2015.00991","article-title":"Quantitative RT-PCR assay for high-throughput screening (HTS) of drugs against the growth of Cryptosporidium parvum in vitro","volume":"6","author":"Zhang","year":"2015","journal-title":"Front Microbiol"},{"key":"2022010520143747900_dkab369-B30","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/978-1-4939-9748-0_18","article-title":"High-throughput screening of drugs against the growth of Cryptosporidium parvum in vitro by qRT-PCR","volume":"2052","author":"Zhang","year":"2020","journal-title":"Methods Mol Biol"},{"key":"2022010520143747900_dkab369-B31","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fonc.2014.00040","article-title":"In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies","volume":"4","author":"McDermott","year":"2014","journal-title":"Front Oncol"},{"key":"2022010520143747900_dkab369-B32","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2147\/CMAR.S226410","article-title":"ERalpha36 as a potential therapeutic target for tamoxifen-resistant breast cancer cell line through EGFR\/ERK signaling pathway","volume":"12","author":"Li","year":"2020","journal-title":"Cancer Manag Res"},{"key":"2022010520143747900_dkab369-B33","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1007\/s00204-019-02453-2","article-title":"Overcoming acquired resistance of gefitinib in lung cancer cells without T790M by AZD9291 or Twist1 knockdown in vitro and in vivo","volume":"93","author":"Liu","year":"2019","journal-title":"Arch Toxicol"},{"key":"2022010520143747900_dkab369-B34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1247\/csf.18029","article-title":"CCL20 promotes ovarian cancer chemotherapy resistance by regulating ABCB1 expression","volume":"44","author":"Su","year":"2019","journal-title":"Cell Struct Funct"},{"key":"2022010520143747900_dkab369-B35","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ejps.2018.07.028","article-title":"Reversal of epigenetic aberrations associated with the acquisition of doxorubicin resistance restores drug sensitivity in breast cancer cells","volume":"123","author":"Ponnusamy","year":"2018","journal-title":"Eur J Pharm Sci"},{"key":"2022010520143747900_dkab369-B36","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/bjc.1995.370","article-title":"An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein","volume":"72","author":"Doyle","year":"1995","journal-title":"Br J Cancer"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/77\/1\/124\/41931405\/dkab369.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/77\/1\/124\/41931405\/dkab369.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T20:15:52Z","timestamp":1641413752000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/77\/1\/124\/6397014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,14]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,10,14]]},"published-print":{"date-parts":[[2021,12,24]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkab369","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,1,1]]},"published":{"date-parts":[[2021,10,14]]}}}