Deciphering enemy tactics - the narrow path to an optimal anticancer strategy targeting the Warburg effect - Review

Sep 23, 2026

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Metabolic changes in cancer cells are central to sustaining high growth and proliferation, with many tumors showing elevated glucose uptake and intensified aerobic glycolysis known as the Warburg effect. Through this pathway, cancer cells rapidly generate energy, supply biosynthetic intermediates, and maintain NAD+ availability for oxidized biomass production. Because metabolism-targeting approaches must avoid disrupting basal metabolism in normal cells, the review evaluates protein, enzyme, and pathway candidates offering cancer specificity. It emphasizes personalized therapeutic strategies and highlights database-driven evidence of gene-expression heterogeneity for theranostic targeting.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

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Abstract

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Introduction

Pharmacological Reports (2025) 77:1143–1162 [https://doi.org/10.1007/s43440-025-00768-9](https://doi.org/10.1007/s43440-025-00768-9) REVIEW Deciphering enemy tactics – the narrow path to an optimal anticancer strategy targeting the Warburg effect Kinga A. Kocemba–Pilarczyk1 · Barbara Ostrowska1 · Sonia E. Trojan1 · Paulina Dudzik1 Received: 2 April 2025 / Revised: 25 July 2025 / Accepted: 28 July 2025 / Published online: 1 August 2025 © The Author(s) 2025 Abstract Metabolic changes in cancer cells are crucial for maintaining their high growth and proliferation rate. As a result, many tumors are characterized by high glucose consumption and intensified aerobic glycolysis, a phenomenon known as the Warburg effect. Through the Warburg effect, cancer cells can rapidly acquire energy, obtain intermediates for biosynthesis, and ensure a source of NAD+ for oxidized biomass synthesis. Altered metabolism and the Warburg effect are characteristic features not only of most transformed proliferating cells but also of normal, rapidly dividing cells, thus posing a challenge for potential anticancer strategies disrupting cellular metabolism. Therefore, targeting the Warburg effect requires a carefully considered strategy so as not to affect the basal metabolism of normal cells and prevent the various side effects in the patient commonly observed with classical chemotherapies targeting DNA replication. On the other hand, strategies/ agents that slow metabolic rate are likely to be less toxic to normal cells than to highly metabolically deregulated cancer cells. The aim of this work is to discuss the most optimal approach for inhibiting these favorable metabolic changes in cancer cells while ensuring specificity. The work discusses proteins, enzymes and pathways that, according to the current state of knowledge, can be optimal candidates for cancer specific targeting such as: HK2, PKM2, PFKFB3, PFKFB4, NAD+ de novo metabolism, NADH oxidation, MCT4, MCT1, LDHA and LDHB. In the era of rapid progress in diagnostic tools providing more and more data on molecular changes, the therapeutic strategy should take into account not only the specificity of the cancer, but also a personalized, optimal approach for each individual patient. This article presents an overview, including available databases, showing the heterogeneity of expression of genes involved in metabolic reprogramming among various cancer patients, which clearly suggests the need to develop a specific theranostic approach for targeting the Warburg effect in a personalized manner. Clinical trial number Not applicable. Keywords Cancer metabolism · Warburg effect · Metabolic reprogramming Abbreviations 2–HNA 6PGD ADP AKT ATP 2–hydroxynicotinic acid 6–phosphogluconate dehydrogenase Adenosine diphosphate Protein kinase B (commonly referred to as Akt) Adenosine triphosphate 􀀍 KingaA. Kocemba–Pilarczyk[kinga.kocemba@uj.edu.pl](kinga.kocemba@uj.edu.pl) 1 Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University – Medical College, Kopernika 7, Kraków 31-034, Poland BLBC CD38 CD157 CDK1 DHAP DNA D–2HG EMT FK866 F–2,6–BPG3P G3PS G6PD HCC Basal–like breast cancer Cluster of differentiation 38 Cluster of differentiation 157 Cyclin–dependent kinase 1 Dihydroxyacetone phosphate Deoxyribonucleic acid D–2–hydroxyglutarate Epithelial–mesenchymal transition A specific NAMPT inhibitor Fructose–2, 6–bisphosphate Glycerol–3–phosphate Glycerol–3–phosphate shuttle Glucose–6–phosphate dehydrogenase Hepatocellular carcinoma HEK293 HIF1 HK1 HK2 HK3 HK4 HKDC1 IDH IDH1/2 KP LDHA LDHB MCT1 MCT4 MAS MDH1 ME ME1 ME2 ME3 MPC NA NAAD NAM NAMPT NAD⁺ NADH NADPH NAD⁺ salvage pathway NAPRT NMNAT NSCLC OS OSCC PARPs PFK–I PFK–II PFKFB1 PFKFB2 Human embryonic kidney 293 cells Hypoxia–inducible factor 1 Hexokinase 1 Hexokinase 2 Hexokinase 3 Hexokinase

FAQs

What is the Warburg effect and why is it important in cancer metabolism?

The Warburg effect is characterized by increased glucose consumption and intensified aerobic glycolysis. It enables cancer cells to rapidly acquire energy, obtain biosynthesis intermediates, and secure NAD+ for oxidized biomass synthesis.

Why are metabolism-targeting anticancer strategies considered challenging?

Targeting the Warburg effect must be carefully designed to avoid affecting the basal metabolism of normal cells. The review contrasts this need with side effects commonly seen in classical chemotherapies that target DNA replication.

Which targets and pathways does the review discuss for cancer-specific inhibition?

The review discusses candidate proteins, enzymes, and pathways including HK2, PKM2, PFKFB3, PFKFB4, NAD+ de novo metabolism, NADH oxidation, MCT4, MCT1, LDHA, and LDHB.

Sep 23, 2026

Uploaded by Kurz