Volume 32, Issue 3 (Autumn 2025)                   Journal of Translational Medical Research. 2025, 32(3): 196-208 | Back to browse issues page

Research code: 6663
Ethics code: IR.BUMS.REC.1403.342


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Mesbah Mousavi A, Khorashadizadeh M, Zarban A, Chamani E. The effects of High and Low-PAD Score (Based on Phenolic level, Antioxidant level and Diastase activity) honey on Lactate Dehydrogenase (LDH) activity level and glucose consumption in 5-Fluorouracil Treated HT-29 Cells: An in vitro study. Journal of Translational Medical Research. 2025; 32 (3) :196-208
URL: http://journal.bums.ac.ir/article-1-3550-en.html
1- Student Research Committee, Birjand University of Medical Science, Birjand, Iran
2- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran & Department of Medical Biotechnology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
3- Department of Clinical Biochemistry, School of Medicine, Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
4- Geriatric Health Research Center, Birjand University of Medical Sciences, Birjand, Iran , chamani.elham@bums.ac.ir
Abstract:   (617 Views)
Background and Aims: Resistance to 5-fluorouracil (5-FU) is a significant challenge in the treatment of colorectal cancer. Metabolic factors in the tumor microenvironment, such as elevated glucose concentration, contribute to this resistance. This study aimed to evaluate the effects of honey with different PAD scores (Phenolic level, Antioxidant level, Diastase activity) on HT-29 cell response to 5-FU and their association with lactate dehydrogenase (LDH) activity and glucose consumption.
Materials and Methods: In this in vitro study, HT-29 cells were cultured under two conditions: normal glucose (Normal Glc) and high glucose (High Glc). Experimental groups included: 5-FU alone; 5-FU combined with High-PAD score and Low-PAD score honey; honey alone (High-PAD score and Low-PAD score); untreated controls; and 5-FU under High Glc. The MTT assay assessed cell viability, while glucose consumption and LDH activity were measured using commercial kits. All experiments were performed in triplicate. Statistical analyses were conducted using SPSS software (version 19) using one-way ANOVA and t-tests (P≤0.05).
Results: The IC50 of 5-FU increased 2.2-fold in High Glc (110 μM), compared to Normal Glc (50 μM). In Normal Glc, combining 5-FU with High-PAD score and Low-PAD score honey reduced the IC50 to 25 μM. The highest normalized LDH activity (0.8226±0.0096) and the most significant decrease in extracellular glucose (10±1.41 mg/dL) were observed in the 5-FU+High-PAD score honey group. The High Glc control exhibited elevated LDH (~0.83) but much higher residual glucose (298.5 mg/dL).
Conclusion: Co-administration of 5-FU with honey, particularly high-PAD score honey, can mitigate drug resistance, likely by increasing glucose consumption and LDH activity.
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Type of Study: Original Article | Subject: Biochemistry- Genetics
Received: 2025/09/12 | Accepted: 2025/10/30 | ePublished ahead of print: 2025/12/24 | ePublished: 2025/11/11

References
1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63. URL: https://pubmed.ncbi.nlm.nih.gov/38572751/ [DOI:10.3322/caac.21834] [PMID]
2. Van der Jeught K, Xu H-C, Li Y-J, Lu X-B, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834. https://pubmed.ncbi.nlm.nih.gov/30228778/ [DOI:10.3748/wjg.v24.i34.3834] [PMID] []
3. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-8. URL: https://pubmed.ncbi.nlm.nih.gov/12724731/ [DOI:10.1038/nrc1074] [PMID]
4. Zhang N, Yin Y, Xu S-J, Chen W-S. 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules. 2008;13(8):1551-69. URL: https://pubmed.ncbi.nlm.nih.gov/18794772/ [DOI:10.3390/molecules13081551] [PMID] []
5. Zhao H, Wu K. Effect of hyperglycemia on the occurrence and prognosis of colorectal cancer. Am J Transl Res. 2024;16(5):2070. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC11170586/ [DOI:10.62347/NYHH3132] [PMID] []
6. Wang M, Zhou Q, Cao T, Li F, Li X, Zhang M, et al. Lactate dehydrogenase A: a potential new target for tumor drug resistance intervention. J Transl Med. 2025; 23(1): 713. https://doi.org/10.1186/s12967-025-06773-z [DOI:10.1186/s12967-023-04547-z] [PMID] []
7. Zhang Q, Luo Y, Qian B, Cao X, Xu C, Guo K, et al. A systematic pan-cancer analysis identifies LDHA as a novel predictor for immunological, prognostic, and immunotherapy resistance. Aging (Albany NY). 2024;16(9):8000-18. URL: https://pubmed.ncbi.nlm.nih.gov/38709280/ [DOI:10.18632/aging.205800]
8. Zhang K, Zhang T, Yang Y, Tu W, Huang H, Wang Y, et al. N6-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming. Theranostics. 2022;12(10):4802-17. URL: https://pubmed.ncbi.nlm.nih.gov/35832094/ [DOI:10.7150/thno.73746] [PMID] []
9. Wu J, Chen J, Xi Y, Wang F, Sha H, Luo L, et al. High glucose induces epithelial-mesenchymal transition and results in the migration and invasion of colorectal cancer cells. Exp Ther Med. 2018;16(1):222-30. URL: https://pubmed.ncbi.nlm.nih.gov/29896243/ [DOI:10.3892/etm.2018.6189]
10. Li W, Zhang X, Sang H, Zhou Y, Shang C, Wang Y, et al. Effects of hyperglycemia on the progression of tumor diseases. J Exp Clin Cancer Res. 2019;38(1):327. URL: https://pubmed.ncbi.nlm.nih.gov/31337431/ [DOI:10.1186/s13046-019-1309-6] [PMID] []
11. Al Refaey HR, Newairy A-SA, Wahby MM, Albanese C, Elkewedi M, Choudhry MU, et al. Manuka honey enhanced sensitivity of HepG2, hepatocellular carcinoma cells, for Doxorubicin and induced apoptosis through inhibition of Wnt/β-catenin and ERK1/2. Biol Res. 2021;54(1):16. URL: https://pubmed.ncbi.nlm.nih.gov/34049576/ [DOI:10.1186/s40659-021-00339-1] [PMID] []
12. Karbasi S, Asadian AH, Azaryan E, Naseri M, Zarban A. Quantitative analysis of biochemical characteristics and anti-cancer properties in MCF-7 breast cancer cell line: a comparative study between Ziziphus jujube honey and commercial honey. Mol Biol Rep. 2024;51(1):344. URL: https://pubmed.ncbi.nlm.nih.gov/38400882/ [DOI:10.1007/s11033-024-09219-9] [PMID]
13. Mohammadi Y, Tahergorabi Z, Sharifzadeh GR, Rajabi Moghadam M, Zarban A. Protective Effects of Some Graded Iranian Honey Samples Against Cold Water Immersion‐Induced Gastric Ulcers in Rats.Food Sci Nutr. 2024;12(12):10211-22. URL: https://pubmed.ncbi.nlm.nih.gov/39723096/ [DOI:10.1002/fsn3.4567] [PMID] []
14. Blake DA, McLean NV. A colorimetric assay for the measurement of D-glucose consumption by cultured cells. Anal Biochem. 1989;177(1):156-60. URL: https://pubmed.ncbi.nlm.nih.gov/2742145/ [DOI:10.1016/0003-2697(89)90031-6] [PMID]
15. Hulme C, Westwood M, Myers J, Heazell A. A high-throughput colorimetric-assay for monitoring glucose consumption by cultured trophoblast cells and placental tissue. Placenta. 2012;33(11): 949-51. URL: https://pubmed.ncbi.nlm.nih.gov/22951137/ [DOI:10.1016/j.placenta.2012.08.001] [PMID]
16. TeSlaa T, Teitell MA. Techniques to monitor glycolysis. Methods Enzymol. 2014; 542: 91-114. URL: https://pubmed.ncbi.nlm.nih.gov/24862262/ [DOI:10.1016/B978-0-12-416618-9.00005-4] [PMID] []
17. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. URL: https://pubmed.ncbi.nlm.nih.gov/33538338/ [DOI:10.3322/caac.21660] [PMID]
18. Bergandi L, Mungo E, Morone R, Bosco O, Rolando B, Doublier S. Hyperglycemia promotes chemoresistance through the reduction of the mitochondrial DNA damage, the Bax/Bcl-2 and Bax/Bcl-XL ratio, and the cells in Sub-G1 phase due to antitumoral drugs induced-cytotoxicity in human colon adenocarcinoma cells.Front Pharmacol. 2018;9:866. URL: https://pubmed.ncbi.nlm.nih.gov/30150934/ [DOI:10.3389/fphar.2018.00866] [PMID] []
19. Lu Y-n. Blocking lncRNA NOP14-AS1 overcomes 5-Fu resistance of colon cancer cells by modulating miR-30a-5p-LDHA-glucose metabolism pathway. Discov Oncol. 2025;16(1):1-12. URL: https://pubmed.ncbi.nlm.nih.gov/40180667/ [DOI:10.1007/s12672-025-02156-4] [PMID] []
20. Afrin S, Giampieri F, Forbes-Hernández TY, Gasparrini M, Amici A, Cianciosi D, et al. Manuka honey synergistically enhances the chemopreventive effect of 5-fluorouracil on human colon cancer cells by inducing oxidative stress and apoptosis, altering metabolic phenotypes and suppressing metastasis ability. Free Radic Biol Med. 2018;126:41-54. URL: https://pubmed.ncbi.nlm.nih.gov/30056083/ [DOI:10.1016/j.freeradbiomed.2018.07.014] [PMID]
21. Cianciosi D, Forbes-Hernández TY, Afrin S, Gasparrini M, Reboredo-Rodriguez P, Manna PP, et al. Phenolic compounds in honey and their associated health benefits: A review. Molecules. 2018;23(9):2322. URL: https://pubmed.ncbi.nlm.nih.gov/30208664/ [DOI:10.3390/molecules23092322] [PMID] []
22. Waheed M, Hussain MB, Javed A, Mushtaq Z, Hassan S, Shariati MA, et al. Honey and cancer: A mechanistic review. Clin Nutr. 2019;38(6):2499-503. URL: https://pubmed.ncbi.nlm.nih.gov/30639116/ [DOI:10.1016/j.clnu.2018.12.019] [PMID]
23. Chan FK-M, Moriwaki K, De Rosa MJ. Detection of necrosis by release of lactate dehydrogenase activity. Immune Homeostasis: Methods Mol Biol. 2013:979: 65-70. URL: https://pubmed.ncbi.nlm.nih.gov/23397389/ [DOI:10.1007/978-1-62703-290-2_7] [PMID] []
24. Fotakis G, Timbrell JA. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett. 2006;160(2):171-7. URL: https://pubmed.ncbi.nlm.nih.gov/16111842/ [DOI:10.1016/j.toxlet.2005.07.001] [PMID]
25. Xiang J, Zhang H, Shen K, Feng J, Yang K, Shi T, et al. SPARC Promotes Aerobic Glycolysis and 5‐Fluorouracil Resistance in Colorectal Cancer Through the STAT3/HK2 Axis. Cancer Med. 2025;14(11):e70972. URL: https://pubmed.ncbi.nlm.nih.gov/40415238/ [DOI:10.1002/cam4.70972] [PMID] []
26. Denise C, Paoli P, Calvani M, Taddei ML, Giannoni E, Kopetz S, et al. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget. 2015;6(39):41706. URL: https://pubmed.ncbi.nlm.nih.gov/26527315/ [DOI:10.18632/oncotarget.5991] [PMID] []

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