Iranian
Biomedical Journal
Volume 29, Issue 6 (11-2025)
IBJ 2025, 29(6): 427-436 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Kahrizi A, Asgarian-Omran H, Taghiloo S, Valadan R, Najafi A, Akbar A, et al . Targeting Metabolic Pathways in AML Cell Lines: Impact of Hypoxia-Inducible Factor-1α (HIF-1α) and Lactate Dehydrogenase-A (LDH-A) Inhibition. IBJ 2025; 29 (6) :427-436
URL: http://ibj.pasteur.ac.ir/article-1-5155-en.html
URL: http://ibj.pasteur.ac.ir/article-1-5155-en.html
Amir Kahrizi 
, Hossein Asgarian-Omran , Saeid Taghiloo , Reza Valadan , Ahmad Najafi , Armin Akbar , Ehsan Zaboli , Ramin Shekarriz , Mohammad Eslami-Jouybari , Mohsen Tehrani *
, Hossein Asgarian-Omran , Saeid Taghiloo , Reza Valadan , Ahmad Najafi , Armin Akbar , Ehsan Zaboli , Ramin Shekarriz , Mohammad Eslami-Jouybari , Mohsen Tehrani *
Abstract:
Introduction: The Warburg effect is considered one of the most important metabolic alterations in tumor cells. While extensively studied in solid tumors, the role of this effect in acute myeloid leukemia (AML) is less defined. hypoxia inducible factor 1 alpha (HIF-1α) and lactate dehydrogenase A (LDH-A) are key regulators of glycolysis, promoting lactate production and the expression of lactate transporters. In this study, we examined the impact of HIF-1α and LDH-A inhibition on metabolic pathways, cell viability, and lactate transporter mRNA expression in AML cell lines.
Methods: K-562 and HL-60 cells were treated with silibinin, an HIF-1α inhibitor, and sodium oxamate, a LDH-A inhibitor. Cell viability and apoptosis were evaluated using the MTT assay and flow cytometry, respectively. Acidification rate and LDH-A activity were assessed using lactate assay and LDH-A assay kits, respectively. Relative mRNA expression of MCT1 and MCT4 was determined using qRT-PCR.
Results: Treatment with silibinin and sodium oxamate reduced proliferation and increased apoptosis in both K-562 and HL-60 cells. As expected, both agents decreased extracellular lactate release in K-562 cells, and sodium oxamate inhibited the LDH-A activity in both cell lines. Interestingly, the expression of MCT1, but not MCT4, was downregulated in K-562 cells after treatment.
Conclusion: Our findings show that HIF-1α and LDH-A inhibitors not only serve as cytotoxic drugs but also regulate the expression of lactate transporter and interfere with the metabolism-related mechanisms in AML cells.
Methods: K-562 and HL-60 cells were treated with silibinin, an HIF-1α inhibitor, and sodium oxamate, a LDH-A inhibitor. Cell viability and apoptosis were evaluated using the MTT assay and flow cytometry, respectively. Acidification rate and LDH-A activity were assessed using lactate assay and LDH-A assay kits, respectively. Relative mRNA expression of MCT1 and MCT4 was determined using qRT-PCR.
Results: Treatment with silibinin and sodium oxamate reduced proliferation and increased apoptosis in both K-562 and HL-60 cells. As expected, both agents decreased extracellular lactate release in K-562 cells, and sodium oxamate inhibited the LDH-A activity in both cell lines. Interestingly, the expression of MCT1, but not MCT4, was downregulated in K-562 cells after treatment.
Conclusion: Our findings show that HIF-1α and LDH-A inhibitors not only serve as cytotoxic drugs but also regulate the expression of lactate transporter and interfere with the metabolism-related mechanisms in AML cells.
Type of Study: Full Length/Original Article |
Subject:
Molecular Immunology & Vaccines
References
1. Saultz JN, Garzon R. Acute myeloid leukemia: A concise review. J Clin Med. 2016;5(3):33. [DOI:10.3390/jcm5030033]
2. Liu H. Emerging agents and regimens for AML. J Hematol Oncol. 2021;14(1):49. [DOI:10.1186/s13045-021-01062-w]
3. Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase A in cancer: A promising target for diagnosis and therapy. IUBMB Life. 2013;65(11):904-10. [DOI:10.1002/iub.1216]
4. Li Z, Wang Q, Huang X, Yang M, Zhou S, Li Z, et al. Lactate in the tumor microenvironment: A rising star for targeted tumor therapy. Front Nutr. 2023;10:1113739. [DOI:10.3389/fnut.2023.1113739]
5. Cui XG, Han ZT, He SH, Wu XD, Chen TR, Shao CH, et al. HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget. 2017;8(15):24840-52. [DOI:10.18632/oncotarget.15266]
6. Parks SK, Pouysségur J. Targeting pH regulating proteins for cancer therapy-Progress and limitations. Semin Cancer Biol. 2017;43:66-73. [DOI:10.1016/j.semcancer.2017.01.007]
7. Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther. 2020;206:107451. [DOI:10.1016/j.pharmthera.2019.107451]
8. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006;281(14):9030-7. [DOI:10.1074/jbc.M511397200]
9. Liu X, Qin H, Zhang L, Jia C, Chao Z, Qin X, et al. Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer. Redox Biol. 2023;61:102647. [DOI:10.1016/j.redox.2023.102647]
10. Valadan R, Hedayatizadeh-Omran A, Alhosseini-Abyazani MN, Amjadi P, Rafiei A, Tehrani M, et al. Data supporting the design and evaluation of a universal primer pair for pseudogene-free amplification of HPRT1 in real-time PCR. Data in Brief. 2015;4:384-9. [DOI:10.1016/j.dib.2015.06.009]
11. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. [DOI:10.1093/nar/29.9.e45]
12. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452(7184):230-3. [DOI:10.1038/nature06734]
13. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010;107(5):2037-42. [DOI:10.1073/pnas.0914433107]
14. Mohammad GH, Vassileva V, Acedo P, Olde Damink SWM, Malago M, Dhar DK, et al. Targeting pyruvate kinase M2 and lactate dehydrogenase A is an effective combination strategy for the treatment of pancreatic cancer. Cancers (Basel). 2019;11(9):1372. [DOI:10.3390/cancers11091372]
15. Kwak C-H, Jin L, Han JH, Han CW, Kim E, Cho M, et al. Ilimaquinone induces the apoptotic cell death of cancer cells by reducing pyruvate dehydrogenase kinase 1 activity. Int J Mol Sci. 2020;21(17):6021. [DOI:10.3390/ijms21176021]
16. Infantino V, Santarsiero A, Convertini P, Todisco S, Iacobazzi V. Cancer cell metabolism in hypoxia: Role of HIF-1 as key regulator and therapeutic target. Int J Mol Sci. 2021;22(11):5703. [DOI:10.3390/ijms22115703]
17. Aprile M, Cataldi S, Perfetto C, Federico A, Ciccodicola A, Costa V. Targeting metabolism by B-raf inhibitors and diclofenac restrains the viability of BRAF-mutated thyroid carcinomas with Hif-1α-mediated glycolytic phenotype. Br J Cancer. 2023;129(2):249-65. [DOI:10.1038/s41416-023-02282-2]
18. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001;93(4):309-14. [DOI:10.1093/jnci/93.4.309]
19. Feng W, Xue T, Huang S, Shi Q, Tang C, Cui G, et al. HIF-1α promotes the migration and invasion of hepatocellular carcinoma cells via the IL-8-NF-κB axis. Cell Mol Biol Lett. 2018;23:26. [DOI:10.1186/s11658-018-0077-1]
20. Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C, et al. Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 2008;99(1):121-8. [DOI:10.1111/j.1349-7006.2007.00643.x]
21. Sellam LS, Zappasodi R, Chettibi F, Djennaoui D, Yahi-Ait Mesbah N, Amir-Tidadini ZC, et al. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys. 2020;690:108479. [DOI:10.1016/j.abb.2020.108479]
22. Zhang W, Wang C, Hu X, Lian Y, Ding C, Ming L. Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells. Oncol Rep. 2022;47(4):77. [DOI:10.3892/or.2022.8288]
23. Shukla SK, Dasgupta A, Mehla K, Gunda V, Vernucci E, Souchek J, et al. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth. Oncotarget. 2015;6(38):41146-61. [DOI:10.18632/oncotarget.5843]
24. Yang Y, Su D, Zhao L, Zhang D, Xu J, Wan J, et al. Different effects of LDH-A inhibition by oxamate in non-small cell lung cancer cells. Oncotarget. 2014;5(23):11886-96. [DOI:10.18632/oncotarget.2620]
25. Choi S-H, Kim M-Y, Yoon Y-S, Koh D-I, Kim M-K, Cho S-Y, et al. Hypoxia-induced RelA/p65 derepresses SLC16A3(MCT4) by downregulating ZBTB7A. Biochim Biophys Acta Gene Regul Mech. 2019;1862(8):771-85. [DOI:10.1016/j.bbagrm.2019.06.004]
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
IBJ is a member of Committee on Publication Ethics (COPE)
and follows its guidelines |
The articles of this journal are licensed under
a Creative Commons Attribution-NonDerivatives 4.0 International License. .png) |
 IBJ is owned and published by Pasteur Institute of Iran |