AccScience Publishing / CP / Online First / DOI: 10.36922/cp.8363
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ORIGINAL RESEARCH ARTICLE

Breaking the metabolic code in triple-negative breast cancer: Mechanistic insights into glycolytic enzyme inhibitors for suppressing metastasis and tumor growth

Samina Malik1 ,  Arif Malik2,3* ,  Jehanzaib Islam4 ,  Haleema Saadia5 ,  Gul Zaib2 ,  Ayesha Zahid2 ,  Abdul Rehman Rashid2 ,  Faheem Arif6
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1 Department of Physiology, University College of Medicine and Dentistry, The University of Lahore, Lahore, Punjab, Pakistan
2 Department of School of Pain and Regenerative Medicine (SPRM), Faculty of Sciences, The University of Lahore, Lahore, Punjab, Pakistan
3 Department of Pharmacy, Faculty of Health Sciences, Equator University of Science and Technology, Masaka, Uganda
4 Department of Biological Sciences, Faculty of Sciences, Grand Asian University, Sialkot, Punjab, Pakistan
5 Department of Biochemistry, Islam Medical and Dental College, Sialkot, Punjab, Pakistan
6 Department of Pharmacy, Faculty of Pharmacy, The University of Lahore, Lahore, Punjab, Pakistan
CP, 8363 https://doi.org/10.36922/cp.8363
Received: 2 January 2025 | Revised: 17 February 2025 | Accepted: 28 February 2025 | Published online: 17 June 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Triple-negative breast cancer (TNBC) is an aggressive and metastatic form of breast cancer with limited treatment options. Glycolytic enzymes such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) serve as effective targets for metabolic reprogramming in suppressing tumor growth. This study investigates the effects of glycolytic enzyme inhibitors, particularly phytochemicals, on TNBC metastasis and tumor growth using a 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat model. Following TNBC induction, these rats were treated with phytochemical inhibitors: 2-deoxy-D-glucose (2-DG), shikonin, oxamate, kaempferol, quercetin, or luteolin. Molecular docking analysis was conducted to characterize the interactions between these compounds and the glycolytic enzymes HK2, PKM2, and LDHA. Glycolytic enzyme inhibition was inferred from the protein expression levels of HK2, PKM2, and LDHA in different treatment groups. Among the compounds tested, kaempferol showed the highest binding affinity toward glycolytic enzymes HK2 and PKM. In addition, shikonin and kaempferol exhibited cell-line-specific antiglycolytic properties by inhibiting glycolytic enzymes HK2, PKM2, and LDHA, thereby suppressing TNBC growth and metastasis. These results suggest that glycolytic enzymes could serve as potential therapeutic targets for improving TNBC treatment, with possible clinical application alongside primary conventional therapies.

Graphical abstract
Keywords
Shikonin
Kaempferol
Pyruvate kinase M2
Hexokinase 2
Molecular docking
Phytochemicals
Metabolic reprogramming
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Gupta GK, Collier AL, Lee D, et al. Perspectives on triple-negative breast cancer: Current treatment strategies, unmet needs, and potential targets for future therapies. Cancers. 2020;12(9):2392. doi: 10.3390/cancers12092392

 

  1. Obidiro O, Battogtokh G, Akala EO. Triple negative breast cancer treatment options and limitations: Future outlook. Pharmaceutics. 2023;15(7):1796. doi: 10.3390/pharmaceutics15071796

 

  1. Liu S, Li Y, Yuan M, Song Q, Liu M. Correlation between the Warburg effect and progression of triple-negative breast cancer. Front Oncol. 2023;12:1060495. doi: 10.3389/fonc.2022.1060495

 

  1. Godley LA. The Effects of Beta-hydroxybutyrate and Glucose on Breast Cancer Cell Cycle Regulation and Metabolism. Master’s Thesis: York University; 2020. Available from: https://hdl.handle.net/10315/41444.

 

  1. Littleflower AB, Parambil ST, Antony GR, Subhadradevi L. The determinants of metabolic discrepancies in aerobic glycolysis: Providing potential targets for breast cancer treatment. Biochimie. 2024;220:107-107. doi: 10.1016/j.biochi.2024.01.003

 

  1. Frisardi V, Canovi S, Vaccaro S, Frazzi R. The significance of microenvironmental and circulating lactate in breast cancer. Int J Mol Sci. 2023;24(20):15369. doi: 10.3390/ijms242015369

 

  1. Adhikari S, Guha D, Mohan C, Mukherjee S, Tyler JK, Das C. Reprogramming carbohydrate metabolism in cancer and its role in regulating the tumor microenvironment. Subcell Biochem. 2022;100:3-65. doi: 10.1007/978-3-031-07634-3_1

 

  1. Claps G, Faouzi S, Quidville V, et al. The multiple roles of LDH in cancer. Nat Rev Clin Oncol. 2022;19(12):749-762. doi: 10.1038/s41571-022-00686-2.

 

  1. Kaur R, Gupta S, Kulshrestha S, et al. Metabolomics-driven biomarker discovery for breast cancer prognosis and diagnosis. Cells. 2024;14(1):5. doi: 10.3390/cells14010005

 

  1. El-Far AH, Al Jaouni SK, Li X, Fu J. Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics. Phytother Res. 2022;36(8):3181-3191. doi: 10.1002/ptr.7534

 

  1. Khan A, Siddiqui S, Husain SA, et al. Phytocompounds targeting metabolic reprogramming in cancer: An assessment of role, mechanisms, pathways, and therapeutic relevance. J Agric Food Chem. 2021;69(25):6897-6928. doi: 10.1021/acs.jafc.1c01173

 

  1. Varghese E, Samuel SM, Líšková A, Samec M, Kubatka P, Büsselberg D. Targeting glucose metabolism to overcome resistance to anticancer chemotherapy in breast cancer. Cancers (Basel). 2020;12(8):2252. doi: 10.3390/cancers12082252

 

  1. Van Barele M, Heemskerk-Gerritsen BA, Louwers YV, et al. Estrogens and progestogens in triple-negative breast cancer: Do they harm? Cancers. 2021;13(11):2506. doi: 10.3390/cancers13112506

 

  1. Sun X, Wang M, Wang M, et al. Metabolic reprogramming in triple-negative breast cancer. Front Oncol. 2020;10:428. doi: 10.3389/fonc.2020.00428

 

  1. Ciscato F, Ferrone L, Masgras I, et al. Hexokinase 2 in cancer: A prima donna playing multiple characters. Int J Mol Sci. 2021;22(9):4716. doi: 10.3390/ijms22094716

 

  1. Liu B, Lu Y, Taledaohan A, et al. The promoting role of HK II in tumor development and the research progress of its inhibitors. Molecules. 2023;29(1):75. doi: 10.3390/molecules29010075

 

  1. Ros S, Schulze A. Balancing glycolytic flux: The role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab. 2013;1:1. doi: 10.1186/2049-3002-1-8

 

  1. Zagami P, Carey LA. Triple-negative breast cancer: Pitfalls and progress. NPJ Breast Cancer. 2022;8(1):95. doi: 10.1038/s41523-022-00468-0

 

  1. Yu Y, Jiang Y, Glandorff C, et al. Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side. Cell Signal. 2024;120:111239. doi: 10.1016/j.cellsig.2024.111239

 

  1. Varghese R, Dalvi YB. Natural products as anticancer agents. Curr Drug Targets. 2021;22(11):1272-1287. doi: 10.2174/1389450121999201230204526

 

  1. Arundhathi JD, Mathur SR, Gogia A, Deo SV, Mohapatra P, Prasad CP. Metabolic changes in triple-negative breast cancer-focus on aerobic glycolysis. Mol Biol Rep. 2021; 48(5):4733-4745. doi: 10.1007/s11033-021-06414-w

 

  1. Afonso J, Santos LL, Longatto-Filho A, Baltazar F. Competitive glucose metabolism as a target to boost bladder cancer immunotherapy. Nat Rev Urol. 2020;17(2):77-106. doi: 10.1038/s41585-019-0263-6

 

  1. Cui Y, Li C, Sang F, et al. Natural products targeting glycolytic signaling pathways: An updated review on anti-cancer therapy. Front Pharmacol. 2022;13:1035882. doi: 10.3389/fphar.2022.1035882

 

  1. Naik A, Decock J. Lactate metabolism and immune modulation in breast cancer: A focused review on triple-negative breast tumors. Front Oncol. 2020;10:598626. doi: 10.3389/fonc.2020.598626

 

  1. Sharma D, Singh M, Rani R. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin Cancer Biol. 2022;87:184-195. doi: 10.1016/j.semcancer.2022.11.007

 

  1. Chen Q, Han H, Lin F, et al. Novel shikonin derivatives suppress cell proliferation, migration and induce apoptosis in human triple-negative breast cancer cells via regulating PDK1/PDHC axis. Life Sci. 2022;310:121077. doi: 10.1016/j.lfs.2022.121077

 

  1. Masarkar N, Ray SK, Saleem Z, et al. Potential anti-cancer activity of Moringa oleifera derived bio-active compounds targeting hypoxia-inducible factor-1 alpha in breast cancer. J Complement Integr Med. 2024;21(3):282-294. doi: 10.1515/jcim-2023-0182

 

  1. Kaur S, Mendonca P, Soliman KF. The anticancer effects and therapeutic potential of kaempferol in triple-negative breast cancer. Nutrients. 2024;16(15):2392. doi: 10.3390/nu16152392

 

  1. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619-634. doi: 10.1038/nrc.2016.71

 

  1. Mohamed M, Alaaeldin E, Hussein A, Sarhan HA. Liposomes and PEGylated liposomes as drug delivery system. J Adv Biomed Pharm Sci. 2020;3(2):80-88. doi: 10.21608/jabps.2020.22937.1068

 

  1. Attia YM, El-Abhar HS, Al Marzabani MM, et al. Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines. BMC Cancer. 2015;15:838. doi: 10.1186/s12885-015-1850-4

 

  1. Bénéteau M, Zunino B, Jacquin MA, et al. Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response. Proc Natl Acad Sci USA. 2012;109(49):20071-20076. doi: 10.1073/pnas.1206360109

 

  1. Li W, Xu M, Li Y, et al. Comprehensive analysis of the association between tumor glycolysis and immune/ inflammation function in breast cancer. J Transl Med. 2020;18(1):92. doi: 10.1186/s12967-020-02267-2

 

  1. Chouchani ET, Kazak L, Jedrychowski MP, et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature. 2016;532(7597):112-116. doi: 10.1038/nature17399

 

  1. Joffre C. Polyunsaturated fatty acid metabolism in the brain and brain cells. In: Feed your Mind-How does Nutrition Modulate Brain Function Throughout Life? London: IntechOpen; 2019. doi: 10.5772/intechopen.88232

 

  1. Varghese E, Samuel SM, Líšková A, Samec M, Kubatka P, Büsselberg D. Targeting glucose metabolism to overcome resistance to anticancer chemotherapy in breast cancer. Cancers (Basel). 2020;12(8):2252. doi: 10.3390/cancers12082252

 

  1. Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52-79. doi: 10.1016/j.ejpb.2015.03.018.

 

  1. Jiang T, Mo R, Bellotti A, Zhou J. Targeted drug delivery using cationic liposomes in cancer therapy. J Control Release. 2018;277:84-101. doi: 10.1016/j.jconrel.2018.02.014.

 

  1. Niu N, Ye J, Hu Z, Zhang J, Wang Y. Regulative roles of metabolic plasticity caused by mitochondrial oxidative phosphorylation and glycolysis on the initiation and progression of tumorigenesis. Int J Mol Sci. 2023;24(8):7076. doi: 10.3390/ijms24087076

 

  1. Begines B, Ortiz T, Pérez-Aranda M, Martínez G, Merinero M, Argüelles-Arias F, Alcudia A. Polymeric nanoparticles for drug delivery: Recent developments and future prospects. Nanomaterials. 2020;10(7):1403. doi: 10.3390/nano10071403

 

  1. Wang T, Fu Y, Sun S, et al. Exosome-based drug delivery systems in cancer therapy. Chin Chem Lett. 2023;34(2):107508. doi: 10.1016/j.cclet.2022.05.022

 

  1. Iqbal MA, Md S, Sahni JK, Baboota S, Dang S, Ali J. Nanostructured lipid carriers system: Recent advances in drug delivery. J Drug Target. 2012;20(10):813-830. doi: 10.3109/1061186X.2012.716845

 

  1. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23(1):27-47. doi: 10.1016/j.cmet.2015.12.006

 

  1. Liu Y, Zhang Y, Xiang Q, et al. Comprehensive characterization of fatty acid oxidation in triple-negative breast cancer: Focus on biological roles and drug modulation. Eur J Pharmacol. 2025;991:177343. doi: 10.1016/j.ejphar.2025.177343

 

  1. Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368(6487):eaaw5473. doi: 10.1126/science.aaw5473

 

  1. Pezzuto A, Carico E. Role of HIF-1 in cancer progression: Novel insights. A review. Curr Mol Med. 2018;18(6):343-351. doi: 10.2174/1566524018666181109121849

 

  1. Fan S, Wang W, Che W, et al. Nanomedicines targeting metabolic pathways in the tumor microenvironment: Future perspectives and the role of AI. Metabolites. 2025;15(3):201. doi: 10.3390/metabo15030201

 

  1. Pająk B, Zieliński R, Priebe W. The impact of glycolysis and its inhibitors on the immune response to inflammation and autoimmunity. Molecules. 2024;29(6):1298. doi: 10.3390/molecules29061298

 

  1. Garcia SN, Guedes RC, Marques MM. Unlocking the potential of HK2 in cancer metabolism and therapeutics. Curr Med Chem. 2019;26(41):7285-7322. doi: 10.2174/0929867326666181213092652

 

  1. Zhang L, Wei Y, Yuan S, Sun L. Targeting mitochondrial metabolic reprogramming as a potential approach for cancer therapy. Int J Mol Sci. 2023;24(5):4954. doi: 10.3390/ijms24054954

 

  1. De Francesco EM, Cirillo F, Vella V, Belfiore A, Maggiolini M, Lappano R. Triple-negative breast cancer drug resistance, durable efficacy, and cure: How advanced biological insights and emerging drug modalities could transform progress. Expert Opin Ther Targets. 2022;26(6):513-535. doi: 10.1016/j.canlet.2020.03.006

 

  1. Samad MA, Ahmad I, Zughaibi TA, et al. Nanotechnology-based drug delivery for breast cancer treatment: Current applications and future directions. Eur J Med Chem Rep. 2025;12:100268. doi: 10.1016/j.ejmcr.2025.100268

 

  1. Camarda R, Zhou AY, Kohnz RA, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med. 2016;22(4):427-432. doi: 10.1038/nm.4055

 

  1. Park SY, Choi JH, Nam JS. Targeting cancer stem cells in triple-negative breast cancer. Cancers. 2019;11(7):965. doi: 10.3390/cancers11070965

 

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