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Continuous glycolysis elevates lactate and acidifies the tumor microenvironment, contributing to chemo- and radioresistance and poorer patient survival. It also highlights that mitochondrial metabolism and cancer-specific metabolic vulnerabilities enable new therapy concepts. Treatment resistance is linked to enhanced efflux pumps and MDR proteins that require ATP, and metabolism inhibition can both induce cancer cell death and reverse multidrug resistance. Because many anticancer drugs cannot selectively target cancer cells, nanodrug delivery systems are discussed as flexible approaches to improve uptake, accumulation, reduce drug efflux, enhance targeting, co-administer synergistic agents, and extend drug circulation half-life.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/targeting-glucose-metabolism-in-cancer-cells-as-an-approach-to-overcoming-drug-resistance-pharmaceutics-review/384249/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/targeting-glucose-metabolism-in-cancer-cells-as-an-approach-to-overcoming-drug-resistance-pharmaceutics-review/384249.png","ImageObject",300,407,{"name":92,"@type":93},"Aldword","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the Warburg effect and why is it important in cancer drug resistance?","Question",{"text":113,"@type":114},"It is a metabolic shift from oxidative phosphorylation to glycolysis. 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A. Silva 1,2, Bruno Sarmento 1,3,4 and Od½lia Queirâs 1, *  \nCitation: Cunha, A.; Silva, P.M.A.; Sarmento, B.; Queirós, O. Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance. Pharmaceutics 2023, 15, 2610. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)pharmaceutics15112610  \nAcademic Editor: Kenneth K. W. To  \nReceived: 22 September 2023  \nRevised: 27 October 2023  \nAccepted: 8 November 2023  \nPublished: 10 November 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 4585-116 Gandra, Portugal; [andrea.cunha@iucs.cespu.pt](andrea.cunha@iucs.cespu.pt) (A.C.); [patricia.silva@cespu.pt](patricia.silva@cespu.pt) (P.M.A.S.); [bruno.sarmento@i3s.up.pt](bruno.sarmento@i3s.up.pt) (B.S.)  \n2 1H—TOXRUN—One Health Toxicology Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 3810-193 Gandra, Portugal  \n3 i3S—Instituto de Investigaç¢o e Inovaç¢o em Saóde, Universidade do Porto, 4200-135 Porto, Portugal  \n4 INEB—Instituto de Engenharia Biom²dica, Universidade do Porto, 4200-135 Porto, Portugal  \n* Correspondence: [odilia.queiros@iucs.cespu.pt](odilia.queiros@iucs.cespu.pt)  \nAbstract: The “Warburg effect” consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo-and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation.  \nKeywords: tumor microenvironment; tumor metabolism; glycolysis; Warburg effect; resistance; nanoparticles  \n1. Introduction  \nThe conversion of normal cells or benign tissue into neoplastic precursors usually corresponds to malignant transformation. Additional alterations bestow these cells with unlimited proliferative potential, dissemination and metastasis, resulting in tumor progression [1] . In order to sustain the acquired features, metabolic reprogramming is essential. Changes in cellular metabolism promote the fast production of adenosine triphosphate (ATP) and an increase in the synthesis of biomolecules, including nucleotides, lipids and amino acids. Several mechanisms are known to modulate cancer metabolism, which","cbCaidJ8qSHgAEwV","https://ap.wps.com/l/cbCaidJ8qSHgAEwV","pdf",2709082,29,"English","# Abstract\n# Keywords\n# 1. Introduction\n# 2. Glucose Metabolism","[{\"question\":\"What is the Warburg effect and why is it important in cancer drug resistance?\",\"answer\":\"It is a metabolic shift from oxidative phosphorylation to glycolysis. Continuous glycolysis increases lactate and acidifies the tumor microenvironment, contributing to chemo- and radioresistance and worse outcomes.\"},{\"question\":\"How do efflux pumps and MDR proteins drive multidrug resistance?\",\"answer\":\"Cells expressing MDR proteins export chemotherapeutics out of the cell and require ATP to mediate this drug efflux. Therefore, disrupting main energy-producing pathways can help overcome resistance.\"},{\"question\":\"Why are metabolism-targeting nanoparticles considered promising?\",\"answer\":\"Many anticancer drugs cannot distinguish normal from cancer cells. Nanodrug delivery systems can enhance cellular uptake and drug accumulation, reduce efflux, improve targeted delivery, support combination with synergistic agents, and increase drug half-life.\"}]","Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance - pharmaceutics Review | PDF",1790261831,73]