Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms

Tuğba Kul Köprülü

doi:10.18614/dehm.1818612

Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms

Abstract

Backround: A significant challenge in hepatocellular carcinoma (HCC) therapy is cisplatin resistance, often linked to altered energy metabolism, specifically the Warburg effect (aerobic glycolysis). This study investigates the potential of Aloe vera extract (AVE) to overcome this resistance and enhance cisplatin's efficacy. Methods: The effects of AVE, cisplatin, and their combination (CisAVE) on HepG2 cells were assessed using oxygen consumption assays, real-time cell analysis (RTCA), wound healing assays, and transcriptomic sequencing with functional enrichment analysis. Results: Treatment with CisAVE induced a significant metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS), as indicated by increased oxygen consumption. This shift promoted reactive oxygen species (ROS) production and initiated apoptosis, evidenced by the upregulation of pro-apoptotic genes (FAS, NOXA, PUMA). While AVE's antiproliferative effect occurred later than cisplatin's due to its ATP-dependent mechanism, it demonstrated superior antimigratory effects. Crucially, AVE downregulated LUC7L3, a key gene associated with cisplatin resistance. Transcriptomic analysis further revealed activation of detoxification pathways and modulation of processes suggesting a protective effect against cisplatin-induced hepatorenal toxicity. Conclusion: Our findings demonstrate that Aloe vera extract re-sensitizes cisplatin-resistant HCC cells by reversing the Warburg effect, inducing metabolic reprogramming towards OXPHOS, and suppressing the cisplatin resistance marker LUC7L3. This combination strategy presents a promising multi-faceted approach to overcome chemoresistance in HCC.

Keywords

Project Number

No funding was received for conducting this study.

Ethical Statement

Not applicable

References

1. Zhu X-D, Zhao L, Li B, Cheng Y, Sun H-C. Systemic Treatment for Unresectable Hepatocellular Carcinoma: A Surgeon’s Perspective. J Hepatocell Carcinoma. 2025;12:399-413.
2. Zorina ES, Naryzhny SN. Biomarkers of hepatocellular carcinoma: status and prospects. Biomeditsinskaya Khimiya. 2025;71:7–18.
3. Yang H, Li J, Niu Y, Zhou T, Zhang P, Liu Y, et al. Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment. Front Immunol. 2025;16:1494788.
4. Chai B, Xiang D, Zhou G, Zheng C. Pilot study of an arterial enhancement fraction-based model for progression prediction in HCC undergoing chemoembolization. Front Oncol. 2025;15:1489450.
5. Lu M, Wu Y, Xia M, Zhang Y. The role of metabolic reprogramming in liver cancer and its clinical perspectives. Front Oncol. 2024;14:1454161.
6. Moon H, Ro SW. Ras Mitogen-activated Protein Kinase Signaling and Kinase Suppressor of Ras as Therapeutic Targets for Hepatocellular Carcinoma. J Liver Cancer. 2021;21:1–11.
7. Tan W, Luo X, Li W, Zhong J, Cao J, Zhu S, et al. TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. EBioMedicine. 2019;40:446–56.
8. Ouyang X, Feng L, Yao L, Zhang J, Xiao Y, Liu G, et al. A comprehensive analysis of FOX family in HCC and experimental evidence to support the oncogenic role of FOXH1. Aging. 2022;14:2268–86.

9. Li C, Xiao Y, Zhou J, Liu S, Zhang L, Song X, et al. Knockout of onecut2 inhibits proliferation and promotes apoptosis of tumor cells through SKP2-mediated p53 acetylation in hepatocellular carcinoma. Cell Mol Life Sci. 2024;81:469.
10. Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol. 2023;14:46–70.
11. Park SJ, Shin K, Kim I-H, Lee M, Hong TH, Kim H. Exploring the efficacy of fluorouracil and platinum-based chemotherapy in advanced hepatocellular carcinoma to bridge the treatment gap in resource limited settings. Sci Rep. 2025;15:3386.
12. Hamaya S, Oura K, Morishita A, Masaki T. Cisplatin in Liver Cancer Therapy. Int J Mol Sci. 2023;24:10858.
13. Ishikawa T. Future perspectives on the treatment of hepatocellular carcinoma with cisplatin. World J Hepatol. 2009;1:8.
14. Abd Rashid N, Abd Halim SAS, Teoh SL, Budin SB, Hussan F, Adib Ridzuan NR, et al. The role of natural antioxidants in cisplatin-induced hepatotoxicity. Biomed Pharmacother. 2021;144:112328.
15. Florea AM, Büsselberg D. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects. Cancers. 2011;3:1351–71.
16. Wu PY, Hasanah U, Yang S-H, Chen S-Y, Luo Y-H, Chen C-C, et al. Enhancing cisplatin efficacy in hepatocellular carcinoma with selenocystine: The suppression of DNA repair and inhibition of proliferation in hepatoma cells. Chem Biol Interact. 2025;405:111291.
17. Adilieje CM, Ejezie CS, Obianyido H, Ugwu C, Ezeadichie OS, Ejezie F. Concomitant Administration of Aloe Vera Gel and Rifampicin Protects Against Rifampicin Hepatorenal Toxicity in Male Wistar Rats. Niger J Clin Pract. 2024 Dec 1;27(12):1381-1390.
18. Staffieri S, Russo V, Oliva MA, Alborghetti M, Russo M, Arcella A. Aloe-Emodin Overcomes Anti-Cancer Drug Resistance to Temozolomide and Prevents Colony Formation and Migration in Primary Human Glioblastoma Cell Lines NULU and ZAR. Molecules. 2023 Aug 11;28(16):6024.
19. Yu L, Qin J, Zhang M, Gao Y, Zhao Y. Research Progress on the Anti-Liver Cancer Mechanism and Toxicity of Rhubarb Anthraquinone. Drug Des Devel Ther. 2024 Dec 18;18:6089-6113.
20. Koldemir Gündüz M, Kar F, Kaymak G. Papain Induces Apoptosis by Regulating Caspase-3 and Caspase-9 Genes in HepG2 Cells. Osmangazi J Med 2022. 2023;45(1):94-100.
21. Wang H, Chen W, Cui Y, Gong H, Tang A. Anhydroicaritin suppresses tumor progression via the PI3K/AKT signaling pathway in hepatocellular carcinoma. Aging (Albany NY). 2023 15(15):7831-7843. 22. Goedhart J, Luijsterburg MS. VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots. Sci Rep. 2020 Nov 25;10(1):20560.
23. Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, Wu S, Wang Y. SRplot: A free online platform for data visualization and graphing. PLoS One. 2023 Nov 9;18(11):e0294236.
24. Du Y, Cai M, Xing X, Ji J, Yang E, Wu J. PINA 3.0: mining cancer interactome. Nucleic Acids Res. 2021;49:D1351–7.
25. André F, Trinh A, Balayssac S, Maboudou P, Dekiouk S, Malet-Martino M, et al. Metabolic rewiring in cancer cells overexpressing the glucocorticoid-induced leucine zipper protein (GILZ): Activation of mitochondrial oxidative phosphorylation and sensitization to oxidative cell death induced by mitochondrial targeted drugs. Int J Biochem Cell Biol. 2017;85:166–74.
26. Aoki S, Morita M, Hirao T, Yamaguchi M, Shiratori R, Kikuya M, et al. Shift in energy metabolism caused by glucocorticoids enhances the effect of cytotoxic anti-cancer drugs against acute lymphoblastic leukemia cells. Oncotarget. 2017;8:94271–85.
27. Samuels AL, Heng JY, Beesley AH, Kees UR. Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia. Br J Haematol. 2014;165:57–66.
28. Wang L, Zhao X, Fu J, Xu W, Yuan J. The Role of Tumour Metabolism in Cisplatin Resistance. Front Mol Biosci. 2021;8:691795.
29. Wang D, Ye Q, Gu H, Chen Z. The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies. Front Oncol. 2022;12:984560.
30. Mazerska Z, Mróz A, Pawłowska M, Augustin E. The role of glucuronidation in drug resistance. Pharmacol Ther. 2016;159:35–55.
31. Hugonnet M, Singh P, Haas Q, Von Gunten S. The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology. Front Immunol. 2021;12:799861.
32. Xue X, Liu Y, Chen X, Tao B, Liu P, Zhou H, et al. Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment. Front Pharmacol. 2022;13:1064032.
33. Hornsveld M, Dansen TB, Derksen PW, Burgering BMT. Re-evaluating the role of FOXOs in cancer. Semin Cancer Biol. 2018;50:90–100.
34. Raghuwanshi S, Gartel AL. Small-molecule inhibitors targeting FOXM1: Current challenges and future perspectives in cancer treatments. Biochim Biophys Acta BBA - Rev Cancer. 2023;1878:189015.
35. Daniels NJ, Hershberger CE, Gu X, Schueger C, DiPasquale WM, Brick J, et al. Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms. Cell Rep. 2021;35:108989.
36. Zhang X, Guo J, Shi X, Zhou X, Chen Q. LUC7L3 is a downstream factor of SRSF1 and prevents genomic instability. Cell Insight. 2024;3:100170.
37. Jourdain AA, Begg BE, Mick E, Shah H, Calvo SE, Skinner OS, et al. Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS. Mol Cell. 2021;81:1905-1919.e12.
38. Hoskins AA, Rhoads TW. When cells are down on their LUC7L2, alternative splicing rewires metabolism for OXPHOS. Mol Cell. 2021;81:1859–60.

Details

Primary Language

English

Subjects

Medical Genetics (Excl. Cancer Genetics)

Journal Section

Research Article

Authors

Tuğba Kul Köprülü ^*
Türkiye

Publication Date

July 30, 2026

Submission Date

November 6, 2025

Acceptance Date

July 6, 2026

Published in Issue

Year 2026 Volume: 40 Number: 3

DOI

https://doi.org/10.18614/dehm.1818612

IZ

https://izlik.org/JA97UU64UC

Cite

RIS / Bibtex

APA

Kul Köprülü, T. (2026). Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms. Developments and Experiments in Health and Medicine, 40(3), 338-354. https://doi.org/10.18614/dehm.1818612

AMA

1.Kul Köprülü T. Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms. Dev Exp Health Med. 2026;40(3):338-354. doi:10.18614/dehm.1818612

Chicago

Kul Köprülü, Tuğba. 2026. “Aloe Vera Extract Co-Treatment in Hepatocellular Carcinoma Increases Cisplatin Sensitivity by Shifting Energy Metabolism from Glycolysis to Oxidative Phosphorylation and Inhibiting Key Resistance Mechanisms”. Developments and Experiments in Health and Medicine 40 (3): 338-54. https://doi.org/10.18614/dehm.1818612.

EndNote

Kul Köprülü T (July 1, 2026) Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms. Developments and Experiments in Health and Medicine 40 3 338–354.

IEEE

[1]T. Kul Köprülü, “Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms”, Dev Exp Health Med, vol. 40, no. 3, pp. 338–354, July 2026, doi: 10.18614/dehm.1818612.

ISNAD

Kul Köprülü, Tuğba. “Aloe Vera Extract Co-Treatment in Hepatocellular Carcinoma Increases Cisplatin Sensitivity by Shifting Energy Metabolism from Glycolysis to Oxidative Phosphorylation and Inhibiting Key Resistance Mechanisms”. Developments and Experiments in Health and Medicine 40/3 (July 1, 2026): 338-354. https://doi.org/10.18614/dehm.1818612.

JAMA

1.Kul Köprülü T. Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms. Dev Exp Health Med. 2026;40:338–354.

MLA

Kul Köprülü, Tuğba. “Aloe Vera Extract Co-Treatment in Hepatocellular Carcinoma Increases Cisplatin Sensitivity by Shifting Energy Metabolism from Glycolysis to Oxidative Phosphorylation and Inhibiting Key Resistance Mechanisms”. Developments and Experiments in Health and Medicine, vol. 40, no. 3, July 2026, pp. 338-54, doi:10.18614/dehm.1818612.

Vancouver

1.Tuğba Kul Köprülü. Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms. Dev Exp Health Med. 2026 Jul. 1;40(3):338-54. doi:10.18614/dehm.1818612