{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:04:15Z","timestamp":1786122255359,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State University of Novi Pazar","award":["451-03-34\/2026-03\/200252"],"award-info":[{"award-number":["451-03-34\/2026-03\/200252"]}]},{"award":["451-03-34\/2026-03\/200252"],"award-info":[{"award-number":["451-03-34\/2026-03\/200252"]}],"id":[{"id":"https:\/\/ror.org\/00ggq9r86","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Kragujevac Institute for Information Technologies, Kragujevac","award":["451-03-47\/2023-01\/200378"],"award-info":[{"award-number":["451-03-47\/2023-01\/200378"]}]},{"award":["451-03-47\/2023-01\/200378"],"award-info":[{"award-number":["451-03-47\/2023-01\/200378"]}],"id":[{"id":"https:\/\/ror.org\/01mzbks65","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Metabolic reprogramming enables cancer cells to adapt to energetic stress and sustain proliferation. Simultaneous inhibition of glycolysis and mitochondrial respiration has emerged as a promising strategy to overcome metabolic plasticity. This study evaluated the antiproliferative effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) alone and in combination with metformin in human cancer cell lines. Methods: Human cervical carcinoma (HeLa), lung adenocarcinoma (A549), colorectal adenocarcinoma (HT-29), and normal lung fibroblasts (MRC-5) were treated with 2-DG or metformin individually, or with metformin in the presence of a fixed concentration of 2-DG (1 mM). Cell viability was assessed using the sulforhodamine B assay after 24 and 48 h. IC50 values were calculated by nonlinear regression, Dose Reduction Index (DRI) analysis evaluated sensitization to metformin, and molecular docking was performed to investigate interactions with selected metabolic targets. Results: Both 2-DG and metformin inhibited cell proliferation in a concentration- and time-dependent manner. HeLa cells were the most sensitive to glycolytic inhibition, while A549 and HT-29 cells showed moderate susceptibility. Co-treatment with 2-DG significantly enhanced metformin activity, reducing its IC50 in HeLa cells from 6.04 to 2.00 mM after 24 h and from 2.28 to 1.56 mM after 48 h. DRI analysis demonstrated increased sensitivity to metformin in all cancer cell lines, particularly HT-29 and A549, whereas normal MRC-5 fibroblasts remained comparatively less affected. Molecular docking revealed favorable binding of both 2-DG and metformin to proteins involved in cellular energy metabolism. Conclusions: Combined inhibition of glycolysis and mitochondrial respiration potentiates the antiproliferative effects of metformin, increases metabolic vulnerability in cancer cells, and is supported by molecular docking evidence of interactions with metabolic targets, while showing limited toxicity toward normal fibroblasts. These findings support dual metabolic targeting as a promising therapeutic strategy and warrant further mechanistic and in vivo studies.<\/jats:p>","DOI":"10.3390\/cancers18162537","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T09:14:28Z","timestamp":1786094068000},"page":"2537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Metabolic Targeting of Cancer: Lessons from Metformin and 2-Deoxy-D-Glucose Combinations"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5410-1405","authenticated-orcid":false,"given":"Vesna","family":"Zeljkovi\u0107","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slavi\u0161a","family":"Mini\u0107","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2098-9015","authenticated-orcid":false,"given":"Marko","family":"Mladenovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Sciences and Mathematics, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"},{"name":"Department of Chemistry, Faculty of Sciences and Mathematics, University of Ni\u0161, Vi\u0161egradska 33, 18000 Ni\u0161, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7083-2257","authenticated-orcid":false,"given":"Dejan","family":"Milenkovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Science, Institute of Information Technologies, University of Kragujevac, Liceja Kne\u017eevine Srbije 1A, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5964-049X","authenticated-orcid":false,"given":"Zoran","family":"Markovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Sciences and Mathematics, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-6503","authenticated-orcid":false,"given":"Tanja V.","family":"Soldatovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Sciences and Mathematics, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-3740","authenticated-orcid":false,"given":"Vanja","family":"Kunkin","sequence":"additional","affiliation":[{"name":"\u0110or\u0111e Joanovi\u0107 Zrenjanin General Hospital, Dr Vase Savi\u0107a br. 5, 23000 Zrenjanin, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8788-9206","authenticated-orcid":false,"given":"Maja","family":"Karaman","sequence":"additional","affiliation":[{"name":"Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovi\u0107a 2, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The Emerging Hallmarks of Cancer Metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the Origin of Cancer Cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/jcp.20166","article-title":"Molecular and Cellular Regulation of Glucose Transporter (GLUT) Proteins in Cancer","volume":"202","author":"Macheda","year":"2005","journal-title":"J. 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