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Dergiler / Etlik Veteriner Mikrobiyoloji Dergisi / 2026 / Cilt: 36 Sayı: 1

Evaluation of the Cytotoxic Effect of Sorafenib on the HepG2 Cell Line in Different pH Environments

Sedat Gökmen(KASTAMONU UNIVERSITY)0000-0002-4793-3030
Dilek Güvenç(ONDOKUZ MAYIS ÜNİVERSİTESİ)0000-0003-0036-0914
Sayfa
13–21
Yayın Tarihi
2025-07-24
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⚡ TL;DR(1 Cümlede Hızlı Çıkarım)

Bu çalışma alkali bir mikroçevrenin sorafenib'in sitotoksik ve antiproliferatif etkilerini artırdığını göstermiştir.

📌 3 Maddede Bu Makale

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Amaç & Hipotez:Hepatosit karsinomu, kanserle ilişkili ölümlerin üçüncü önde gelen nedenidir.
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Temel Bulgular & Veri:Warburg etkisi nedeniyle kanser hücrelerinin mikroçevresi asidiktir (pH 6,6–6,9).
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Sonuç & Katkı:Bu çalışma alkali bir mikroçevrenin sorafenib'in sitotoksik ve antiproliferatif etkilerini artırdığını göstermiştir.
🔬Tür:Laboratuvar & Saha Deneyi
📍Kapsam:Genişletilmiş Akademik Örneklem
⚙️Değişkenler:HepG2 · proliferasyon · sorafenib

Özet

Hepatosit karsinomu, kanserle ilişkili ölümlerin üçüncü önde gelen nedenidir. FDA onaylı çoklu kinaz inhibitörü olan Sorafenib, ileri hepatosellüler karsinomu tedavi etmek için kullanılır. Warburg etkisi nedeniyle kanser hücrelerinin mikroçevresi asidiktir (pH 6,6–6,9). Bu asidik ortam, hücrenin hayatta kalmasını, çoğalmasını, invazivliğini, metastazını ve kemoterapötik direncini destekler. Amacımız, sorafenibin insan hepatosellüler karsinomu üzerindeki sitotoksik ve antiproliferatif etkilerini farklı pH seviyelerinde belirlemekti. HepG2 hücre hattı insan hepatosellüler karsinomu olarak kullanıldı ve sorafenib'in farklı konsantrasyonları HepG2'ye sırasıyla pH değerleri 6.6, 6.8, 7.2, 7.6 ve 7.8 olan ortamlarda 24 saat boyunca uygulandı. Sorafenibin sitotoksik etkileri WST-8 testi ile belirlendi. Proliferasyon canlı hücre analizi ve bir görüntüleme sistemi kullanılarak değerlendirildi. Sorafenib'in inhibitör konsantrasyon 50 değeri 13.40 μM olarak bulundu. Sorafenib, HepG2 hücreleri üzerinde en güçlü sitotoksik etkiyi pH 7.6'da gösterdi (p<0.05). Proliferasyon testine göre, pH 7.6'da hazırlanan sorafenib, kontrol ve pH 7.2 ve 6.6'da hazırlanan sorafenib ile karşılaştırıldığında proliferasyonda önemli bir azalmaya (15.84±0.53, p<0.001) neden oldu. Bu çalışma alkali bir mikroçevrenin sorafenib'in sitotoksik ve antiproliferatif etkilerini artırdığını göstermiştir.

Abstract

Hepatocellular carcinoma is the third-leading cause of cancer-related deaths. Sorafenib, an FDA-approved multiple kinase inhibitor, is used to treat advanced hepatocellular carcinoma. The microenvironment of cancer cells is acidic (pH 6.6–6.9) due to the Warburg effect. This acidic environment promotes cell survival, proliferation, invasiveness, metastasis, and chemotherapeutic resistance. Our aim was to identify the cytotoxic and antiproliferative effects of sorafenib on human hepatocellular carcinoma at different pH levels. HepG2 cell line was used as a human hepatocellular carcinoma, and different concentrations of sorafenib were applied to HepG2 for 24 hours in media with pH values of 6.6, 6.8, 7.2, 7.6, and 7.8, respectively. The cytotoxic effects of sorafenib were determined with the WST-8 assay. Proliferation was evaluated using live-cell analysis and an imaging system. Sorafenib’s inhibitor concentration 50 value was 13.40 μM. Sorafenib showed the strongest cytotoxic effect on HepG2 cells at pH 7.6 (p<0.05). According to the proliferation test, sorafenib prepared at pH 7.6 induced a significant decrease (15.84±0.53, p<0.001) in proliferation when compared to the control and sorafenib prepared at pH 7.2 and 6.6. This study showed that an alkaline microenvironment increases the cytotoxic and antiproliferative effects of sorafenib.

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Bu Makaleye Atıf Yap

Gökmen, S., Güvenç, D. (2025). Evaluation of the Cytotoxic Effect of Sorafenib on the HepG2 Cell Line in Different pH Environments. Etlik Veteriner Mikrobiyoloji Dergisi, Cilt: 36 Sayı: 1, 13–21. https://doi.org/10.35864/evmd.1662662

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Kaynakça (32)

  1. References Elsayed MM, Mostafa ME, Alaaeldin E, Sarhan HA, Shaykoon MS, Allam S, Ahmed AR, Elsadek BE. (2019) Design and Characterisation of Novel Sorafenib-loaded Carbon Nanotubes with Distinct Tumour-suppressive Activity in Hepatocellular Carcinoma. International J Nanomedicine. 29(14), 8445-8467.
  2. Escudier B, Worden F, Kudo M. (2016) Sorafenib: Key Lessons from over 10 Years of Experience. Expert Rev Anticancer Ther. 19(2), 177-189.
  3. Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ. (2013) Acidity Generated by the Tumor Microenvironment Drives Local Invasion. Cancer Res. 73(5), 1524-1535.
  4. Faes S, Uldry E, Planche A, Santoro T, Pythoud C, Demartines N, Dormond O. (2016) Acidic pH Reduces VEGF-mediated Endothelial Cell Responses by Downregulation of VEGFR-2; Relevance for Anti-angiogenic Therapies. Oncotarget. 7(52), e-86026. https://doi.org/10.18632/oncotarget.13323
  5. Guvenalp N, Guvenc D. (2020) An Evaluation of the Effects of Medium pH on the Viability of the HepG2 Cell Line. Etlik Veterinary Microbiol. 31(2), 107-114.
  6. Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, Tuccitto A, Tagliabue E, Castelli C, Rivoltini L. (2017) Cancer acidity: An Ultimate Frontier of Tumor Immune Escape and a Novel Target of Immunomodulation. Semin Cancer Biol. 43:74-89.
  7. Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, Li X, Cao K, Deng H, He Y, Liao Q, Xiang B, Zhou M, Guo C, Zeng Z, Li G, Li X, Xiong W. (2020) The role of Microenvironment in Tumor Angiogenesis. J Exp Clin Cancer Res. 39(1), 1-19.
  8. Justus CR, Dong L, Yang LV. (2013) Acidic Tumor Microenvironment and pH-sensing G protein-Coupled Receptors. Front Physiol. 4:e354.
  9. Keating GM. (2017) Sorafenib: A Review in Hepatocellular Carcinoma. Target Oncol. 2(2), 243-253. Koppenol WH, Bounds PL, Dang CV. (2011) Otto Warburg's Contributions to Current Concepts of Cancer Metabolism. Nat Rev Cancer. 11(5), 325-337.
  10. Li W, Zhou Y, Shang C, Sang H, Zhu H. (2020) Effects of Environmental pH on the Growth of Gastric Cancer Cells. Gastroenterol Res Pract. 9, e3245359.
  11. Li XN, Yang SQ, Li M, Li XS, Tian Q, Xiao F, Tang YY, Kang X, Wang CY, Zou W, Zhang P, Tang XQ. (2021) Formaldehyde Induces ferroptosis in Hippocampal Neuronal Cells by Upregulation of the Warburg effect. Toxicology. 448, 152650.
  12. Liu Y, Liu J, Cheng LF, Fan L, Yu H, Sun G. (2017) Melatonin Increases the Anti-tumor Effects of Sorafenib on Human Hepatoma Cell Lines Via down-regulating Autophagy. International Journal of Clinical and Experimental Medicine. 10, 14109-14120.
  13. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. (2021) Hepatocellular Carcinoma. Nat Rev Dis Primers. 7(6), 1-28.
  14. Lotz C, Kelleher DK, Gassner B, Gekle M, Vaupel P, Thews O. (2007) Role of the Tumor Microenvironment in the Activity and Expression of the P-glycoprotein in Human Colon Carcinoma Cells. Oncol Rep. 17(1), 239-244.
  15. Méndez Blanco C, Fondevila F, García Palomo A, González Gallego J, Mauriz JL. (2018) Sorafenib Resistance in Hepatocarcinoma: Role of Hypoxia-inducible Factors. Exp Mol Med. 50(10), 1-9.
  16. Parsons HM, Chu Q, Karlitz JJ, Stevens JL, Harlan LC. (2017) Adoption of Sorafenib for the Treatment of Advanced-stage Hepatocellular Carcinoma in Oncology Practices in the United States. Liver Cancer. 6(3), 216-226.
  17. Patresan J, Patel H, Chandrasekaran K, Reynolds G. (2024) Current Treatment Paradigm and Approach to Advanced Hepatocellular Carcinoma. Cureus. 16(12):e75471.
  18. Pellegrini P, Serviss JT, Lundbäck M, Bancaro N, Mazurkiewicz M, Kolosenko I, Milito A. (2018) A Drug Screening Assay on Cancer Cells Chronically Adapted to Acidosis. Cancer Cell Int. 18(1), 1-15.
  19. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mulé JJ, Ibrahim-Hashim A, Gillies RJ. (2016) Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy. Cancer Res. 76(6), 1381-1390.
  20. Prieto-Domínguez N, Ordóñez R, Fernández A, García-Palomo A, Muntané J, González-Gallego J, Mauriz JL. (2016) Modulation of Autophagy by Sorafenib: Effects on Treatment Response. Front Pharmacol. 8(7), 151.
  21. Rabiee S, Tavakol S, Barati M, Joghataei MT. (2019) Autophagic, Apoptotic, and Necrotic Cancer Cell Fates Triggered by Acidic pH Microenvironment. J Cell Physiol. 234(7), 12061-12069.
  22. Raghunand N, Mahoney BP, Gillies RJ. (2003) Tumor Acidity, Ion Trapping and Chemotherapeutics: II. pH-dependent Partition Coefficients Predict Importance of Ion Trapping on Pharmacokinetics of Weakly Basic Chemotherapeutic Agents. Biochem Pharmacol. 66(7), 1219-1229.
  23. Rich NE. (2024) Changing Epidemiology of Hepatocellular Carcinoma Within the United States and Worldwide. Surg Oncol Clin. 33(1), 1-12.
  24. San Millán I, Brooks GA. (2007) Reexamining Cancer Metabolism: Lactate Production for Carcinogenesis could be the Purpose and Explanation of the Warburg Effect. Carcinogenesis. 38(2), 119-133.
  25. Schwartz L, Supuran CT, Alfarouk KO. (2017) The Warburg Effect and the Hallmarks of Cancer. Anti-Cancer Agents Med Chem. 17(2), 164-170.
  26. Suo A, Zhang M, Yao Y, Zhang Y, Huang C, Nan K, Zhanq W. (2012) Proteome Analysis of the Effects of Sorafenib on Human Hepatocellular Carcinoma Cell Line HepG2. Med Oncol. 29(3), 1827-1836.
  27. Thews O, Gassner B, Kelleher DK, Schwerdt G, Gekle M. (2006) Impact of Extracellular Acidity on the Activity of P-glycoprotein and the Cytotoxicity of Chemotherapeutic Drugs. Neoplasia. 8(2), 143-152.
  28. Tian XP, Wang CY, Jin XH, Li M, Wang FW, Huang WJ, Yun JP, Xu RH, Cai QQ, Xie D. (2019) Acidic Microenvironment up-regulates Exosomal miR-21 and miR-10b in Early-stage Hepatocellular Carcinoma to Promote Cancer Cell Proliferation and Metastasis. Theranostics 9(7), 1965-1979.
  29. Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ. (2011) Drug Resistance and Cellular Adaptation to Tumor Acidic pH Microenvironment. Mol Pharmaceutics. 8(6), 2032-2038.
  30. Yau T, Pang R, Chan P, Poon RT. (2010) Molecular Targeted Therapy of Advanced Hepatocellular Carcinoma beyond Sorafenib. Expert Opin Pharmacother. 11(13), 2187-2198.
  31. Yu B, Ma W. (2024) Biomarker Discovery in Hepatocellular Carcinoma (HCC) for Personalized Treatment and Enhanced Prognosis. Cytokine Growth Factor Rev. 79, 29-38.
  32. Yuan YH, Zhou CF, Yuan J, Liu L, Guo XR, Wang XL, Ding Y, Wang XN, Li DS, Tu HJ. (2016) NaHCO3 Enhances the Antitumor Activities of Cytokine-induced Killer Cells against Hepatocellular Carcinoma HepG2 cells