The effect of neopterin alone or in combination with doxorubicin, cisplatin and vitamin C on the viability of different hepatocellular carcinoma cell lines

Abstract

Hepatocellular carcinoma (HCC) is inflammation-related cancer and the 4^th leading cause of death globally. Neopterin is an instant biomarker of the cellular immune response and belongs to the pteridine class. The levels of neopterin are believed to be very closely linked with the tumor size in patients with HCC. Various studies have proven that neopterin can modulate the cellular oxidant-antioxidant balance, thus causing cell toxicity. In this study, we investigated the cytotoxic effects of neopterin alone and in combination with two of the known cytotoxic agents of doxorubicin and cisplatin together with vitamin C, a well-known antioxidant agent. SNU-449, Hep3B, Mahlavu, and PLC/PRF/5 HCC cell lines were used in this study. Our results showed that increasing concentrations of neopterin does not have any significant effects on the cytotoxicity while as expected the three other agents decrease the viability of all subjected cell lines. SNU-449 is the most resistant HCC cell line among others. Considering the effectivity of combinational therapy in cancer patients, the effect of various combinations of neopterin with doxorubicin, cisplatin and vitamin C on the viability of the most resistant cell line of SNU-449 has been investigated. We found that the addition of cisplatin to the combination of neopterin and vitamin C, causes a greater decrease in cell viability of SNU-449 cells compared to the dual therapy with neopterin and vitamin C, while the addition of doxorubicin to the same dual therapy, leads to a decrease in the effectivity of it.

Keywords

• HCC,neopterin,doxorubicin,cisplatin,vitamin C

References

1. Antoniello S, Auletta M, Magri P, and Russo N 1992. Serum Neopterin Levels in Patients with Hepatocellular Carcinoma. Biological chemistry Hoppe-Seyler 373(11): 1165–68. Capece D , Fischietti M, Verzella D , Gaggiano , Cicciarelli G, Tessitore A, Zazzeroni F, Alesse E 2013. The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages. BioMed research international 2013: 187204.
2. Daher S, Massarwa M, Benson AA, Khoury T 2018. Current and Future Treatment of Hepatocellular Carcinoma: An Updated Comprehensive Review. Journal of clinical and translational hepatology 6(1): 69–78.
3. Godai K, Daito K, Yamada S, Uemasu J, Horie Y, Suou T, Kawasaki H 1994. Clinical Significance of Serum and Urinary Neopterins after Transcatheter Arterial Embolization for Hepatocellular Carcinoma Nihon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 91(6): 1097–1103.
4. Hoffmann G, Kenn S, Wirleitner B, Deetjen C, Frede S, Smolny M, Rieder J, Fuchs D, Baier-Bitterlich G, Schobersberger W 1998. Neopterin Induces Nitric Oxide-Dependent Apoptosis in Rat Vascular Smooth Muscle Cells. Immunobiology 199(1): 63–73.
5. Lv H, Wang C, Fang T, Li T, Lv G, Han Q, Yang W, Wang H 2018. Vitamin C Preferentially Kills Cancer Stem Cells in Hepatocellular Carcinoma via SVCT-2.npj Precision Oncology 2(1): 1.
6. Hoffmann G, Wirleitner B, Fuchs D 2003. Potential Role of Immune System Activation-Associated Production of Neopterin Derivatives in Humans. Inflammation Research 52(8): 313–21.
7. Huber C, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D, Reibnegger G, Swetly P, Troppmair J, Wachter H 1984. Immune Response-Associated Production of Neopterin. Release from Macrophages Primarily under Control of Interferon-Gamma. Journal of Experimental Medicine 160(1): 310–16.
8. Jindal A, Thadi A, Shailubhai K 2019. Hepatocellular Carcinoma: Etiology and Current and Future Drugs. Journal of Clinical and Experimental Hepatology 9(2): 221–32.

9. Lewis M, Merched AJ 2014.Tumor-Associated Macrophages, Inflammation and Pathogenesis of Hepatocellular Carcinoma. Journal of Molecular and Genetic Medicine 08(03).
10. Mazzanti R, Umberto A, and Renato T 2016. Hepatocellular Carcinoma: Where Are We? World journal of experimental medicine 6(1): 21–36.