{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T11:32:46Z","timestamp":1780918366669,"version":"3.54.1"},"reference-count":59,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T00:00:00Z","timestamp":1690934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004748","name":"Mashhad University of Medical Sciences","doi-asserted-by":"publisher","award":["4011318"],"award-info":[{"award-number":["4011318"]}],"id":[{"id":"10.13039\/501100004748","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir\/ritonavir in CRC. The integrative systems biology method and RNAseq were utilized to investigate the differential levels of genes associated with patients with colorectal cancer. The antiproliferative activity of lopinavir\/ritonavir was evaluated in both monolayer and 3-dimensional (3D) models, followed by wound-healing assays. The effectiveness of targeting CYP450 was examined in a mouse model, followed by histopathological analysis, biochemical tests (MDA, SOD, thiol, and CAT), and RT-PCR. The data of dysregulation expressed genes (DEG) revealed 1268 upregulated and 1074 down-regulated genes in CRC. Among the top-score genes and dysregulated pathways, CYPs were detected and associated with poor prognosis of patients with CRC. Inhibition of CYP450 reduced cell proliferation via modulating survivin, Chop, CYP13a, and induction of cell death, as detected by AnnexinV\/PI staining. This agent suppressed the migratory behaviors of cells by induction of E-cadherin. Moreover, lopinavir\/ritonavir suppressed tumor growth and fibrosis, which correlated with a reduction in SOD\/thiol levels and increased MDA levels. Our findings illustrated the therapeutic potential of targeting the CYP450 using lopinavir\/ritonavir in colorectal cancer, supporting future investigations on this novel therapeutic approach for the treatment of CRC.<\/jats:p>","DOI":"10.3390\/cancers15153939","type":"journal-article","created":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T11:17:17Z","timestamp":1690975037000},"page":"3939","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Therapeutic Potential of Targeting the Cytochrome P450 Enzymes Using Lopinavir\/Ritonavir in Colorectal Cancer: A Study in Monolayers, Spheroids and In Vivo Models"],"prefix":"10.3390","volume":"15","author":[{"given":"Maryam","family":"Alaei","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyedeh","family":"Nazari","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghazaleh","family":"Pourali","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AliReza","family":"Asadnia","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5475-4997","authenticated-orcid":false,"given":"Mehrdad","family":"Moetamani-Ahmadi","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Fiuji","sequence":"additional","affiliation":[{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Tanzadehpanah","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad 91779-49367, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8349-3722","authenticated-orcid":false,"given":"Fereshteh","family":"Asgharzadeh","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Babaei","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Khojasteh-Leylakoohi","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Saeed Gataa","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Warith Al-Anbiyaa, Karbala 56001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Ali Kiani","sequence":"additional","affiliation":[{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0957-8349","authenticated-orcid":false,"given":"Gordon","family":"Ferns","sequence":"additional","affiliation":[{"name":"Department of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex BN1 9PH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2771-564X","authenticated-orcid":false,"given":"Alfred","family":"Lam","sequence":"additional","affiliation":[{"name":"Pathology, School of Medicine and Dentistry, Gold Coast Campus, Griffith University, Gold Coast, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed","family":"Hassanian","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Khazaei","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7565-7504","authenticated-orcid":false,"given":"Elisa","family":"Giovannetti","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per La Scienza, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4968-0962","authenticated-orcid":false,"given":"Amir","family":"Avan","sequence":"additional","affiliation":[{"name":"Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran"},{"name":"College of Medicine, University of Warith Al-Anbiyaa, Karbala 56001, Iraq"},{"name":"Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,2]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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