Evaluation of combined use of hsp90 inhibitor mpc-3100 and traditional cancer drug 5-fu on liver cancer cell lines

Year 2023, Issue: 055, 60 - 69, 31.12.2023

Özlem Kaplan

https://doi.org/10.59313/jsr-a.1347817

Cited By: 1

Abstract

Hepatocellular carcinoma (HCC), which constitutes an important part of the global cancer burden, poses an important problem in the field of medicine. Combination therapy targets multiple mechanisms simultaneously using different therapeutic agents together. Heat shock protein 90 (HSP90) inhibitors are emerging as interesting targets in this area, since they play a vital role in the control of cellular processes and impact malignant cell survival and resistance mechanisms. This study evaluated the combined effect of the HSP90 inhibitor MPC-3100 and the traditional chemotherapy drug 5-fluorouracil (5-FU) on HCC. MTT assay was performed to evaluate the individual and combined cytotoxic effects of 5-FU and MPC-3100 on HUH-7 and HepG2 liver cancer cell lines. To assess the effectiveness of combination therapy, the Chou and Talalay method was applied. Both 5-FU and MPC-3100 and 5-FU+ MPC-3100 exhibited dose- and time-dependent cytotoxic effects. Combined administration of the two drugs showed an antagonistic impact on the cell lines. The findings demonstrated that combining 5-FU with MPC-3100 was less effective in inducing cytotoxicity in liver cancer cell lines compared to the use of each drug separately. In this context, the combination of these two drugs in liver cancer is not an appropriate strategy for effective treatment. Current research findings will help design more effective and targeted therapies for HCC and other cancers.

Keywords

MPC-3100, 5-fluorouracil, Combination therapy

Supporting Institution

No supporting

Thanks

The author would like to thank Prof. Dr. İsa GÖKÇE and Dr. Nazan GÖKŞEN TOSUN for contributions.

References

• J. M. Llovet et al., "Hepatocellular carcinoma," Nature Reviews Disease Primers, vol. 7, no. 1, p. 6, 2021/01/21 2021, doi: 10.1038/s41572-020-00240-3.
• Z. Chen et al., "Recent progress in treatment of hepatocellular carcinoma," (in eng), Am J Cancer Res, vol. 10, no. 9, pp. 2993-3036, 2020.
• A. Alqahtani, Z. Khan, A. Alloghbi, T. S. Said Ahmed, M. Ashraf, and D. M. Hammouda, "Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies," (in eng), Medicina (Kaunas), vol. 55, no. 9, Aug 23 2019, doi: 10.3390/medicina55090526.
• R. Bayat Mokhtari et al., "Combination therapy in combating cancer," (in eng), Oncotarget, vol. 8, no. 23, pp. 38022-38043, Jun 6 2017, doi: 10.18632/oncotarget.16723.
• C. Hu et al., "Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities," MedComm, vol. 3, no. 3, p. e161, 2022, doi: 10.1002/mco2.161.
• L. Qin et al., "Biological characteristics of heat shock protein 90 in human liver cancer cells," (in eng), Am J Transl Res, vol. 11, no. 4, pp. 2477-2483, 2019.
• W. Wei et al., "Diagnostic value of plasma HSP90α levels for detection of hepatocellular carcinoma," BMC Cancer, vol. 20, no. 1, p. 6, 2020/01/02 2020, doi: 10.1186/s12885-019-6489-0.
• S.-H. Kim et al., "Discovery of (2S)-1-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a Purine-Based Hsp90 Inhibitor," Journal of Medicinal Chemistry, vol. 55, no. 17, pp. 7480-7501, 2012/09/13 2012, doi: 10.1021/jm3004619.
• S.-H. Kim et al., "Discovery of an l-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100," Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 22, pp. 5254-5257, 2015/11/15/ 2015, doi: 10.1016/j.bmcl.2015.09.053.
• W. E. Samlowski et al., "Abstract A96: Phase 1 study of HSP90 inhibitor MPC-3100 in subjects with refractory or recurrent cancer," Molecular Cancer Therapeutics, vol. 10, no. 11_Supplement, pp. A96-A96, 2011, doi: 10.1158/1535-7163.Targ-11-a96.
• K. Miura et al., "5-fu metabolism in cancer and orally-administrable 5-fu drugs," (in eng), Cancers (Basel), vol. 2, no. 3, pp. 1717-30, Sep 17 2010, doi: 10.3390/cancers2031717.
• M. Terashima et al., "Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines," SpringerPlus, vol. 3, no. 1, p. 417, 2014/08/08 2014, doi: 10.1186/2193-1801-3-417.
• T. Xu et al., "Synergistic Effects of Curcumin and 5-Fluorouracil on the Hepatocellular Carcinoma In vivo and vitro through regulating the expression of COX-2 and NF-κB," (in eng), J Cancer, vol. 11, no. 13, pp. 3955-3964, 2020, doi: 10.7150/jca.41783.
• S. Qin et al., "Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study," (in eng), Oncologist, vol. 19, no. 11, pp. 1169-78, Nov 2014, doi: 10.1634/theoncologist.2014-0190.
• Y. Zhang, L. Jiang, J. Ouyang, X. Du, and L. Jiang, "Efficacy and safety of traditional Chinese medicine injections combined with FOLFOX4 regimen for gastric cancer: A protocol for systematic review and network meta-analysis," (in eng), Medicine (Baltimore), vol. 100, no. 41, p. e27525, Oct 15 2021, doi: 10.1097/md.0000000000027525.
• V. Conteduca et al., "Oxaliplatin plus leucovorin and 5-fluorouracil (FOLFOX-4) as a salvage chemotherapy in heavily-pretreated platinum-resistant ovarian cancer," BMC Cancer, vol. 18, no. 1, p. 1267, 2018/12/19 2018, doi: 10.1186/s12885-018-5180-1.
• D. Anwanwan, S. K. Singh, S. Singh, V. Saikam, and R. Singh, "Challenges in liver cancer and possible treatment approaches," (in eng), Biochim Biophys Acta Rev Cancer, vol. 1873, no. 1, p. 188314, Jan 2020, doi: 10.1016/j.bbcan.2019.188314.
• L. Rinaldi et al., "HCC and Molecular Targeting Therapies: Back to the Future," (in eng), Biomedicines, vol. 9, no. 10, Sep 28 2021, doi: 10.3390/biomedicines9101345.
• J. van Meerloo, G. J. Kaspers, and J. Cloos, "Cell sensitivity assays: the MTT assay," (in eng), Methods Mol Biol, vol. 731, pp. 237-45, 2011, doi: 10.1007/978-1-61779-080-5_20.
• Y. J. Chen, C.-W. Chi, W.-C. Su, and H.-L. Huang, "Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma," Oncotarget, vol. 5, no. 13, p. 4845, 2014.
• Ö. Kaplan et al., "Microwave-assisted green synthesis of silver nanoparticles using crude extracts of Boletus edulis and Coriolus versicolor: Characterization, anticancer, antimicrobial and wound healing activities," Journal of Drug Delivery Science and Technology, vol. 64, p. 102641, 2021/08/01/ 2021, doi: 10.1016/j.jddst.2021.102641.
• G. Schicht, L. Seidemann, R. Haensel, D. Seehofer, and G. Damm, "Critical Investigation of the Usability of Hepatoma Cell Lines HepG2 and Huh7 as Models for the Metabolic Representation of Resectable Hepatocellular Carcinoma," (in eng), Cancers (Basel), vol. 14, no. 17, Aug 30 2022, doi: 10.3390/cancers14174227.
• S. Guariniello, G. Di Bernardo, G. Colonna, M. Cammarota, G. Castello, and S. Costantini, "Evaluation of the Selenotranscriptome Expression in Two Hepatocellular Carcinoma Cell Lines," Analytical Cellular Pathology, vol. 2015, p. 419561, 2015/06/23 2015, doi: 10.1155/2015/419561.
• S. Hussain, J. Schwank, F. Staib, X. Wang, and C. Harris, "TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer," Oncogene, vol. 26, no. 15, pp. 2166-2176, 2007.
• P. Muller, R. Hrstka, D. Coomber, D. P. Lane, and B. Vojtesek, "Chaperone-dependent stabilization and degradation of p53 mutants," Oncogene, vol. 27, no. 24, pp. 3371-3383, 2008/05/01 2008, doi: 10.1038/sj.onc.1211010.
• G. Watanabe, K. E. Behrns, J.-S. Kim, and R. D. Kim, "Heat shock protein 90 inhibition abrogates hepatocellular cancer growth through cdc2-mediated G2/M cell cycle arrest and apoptosis," Cancer Chemotherapy and Pharmacology, vol. 64, no. 3, pp. 433-443, 2009/07/01 2009, doi: 10.1007/s00280-008-0888-2.
• X. Wang et al., "The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: The role of ER stress," Biochemical and Biophysical Research Communications, vol. 446, no. 1, pp. 160-166, 2014/03/28/ 2014, doi: 10.1016/j.bbrc.2014.02.081.
• A. M. Leng et al., "The apoptotic effect and associated signalling of HSP90 inhibitor 17-DMAG in hepatocellular carcinoma cells," Cell Biology International, vol. 36, no. 10, pp. 893-899, 2012, doi: 10.1042/CBI20110473.
• W. Liu et al., "A novel pan-cancer biomarker plasma heat shock protein 90alpha and its diagnosis determinants in clinic," Cancer Science, vol. 110, no. 9, pp. 2941-2959, 2019, doi: 10.1111/cas.14143.
• D. B. Longley, D. P. Harkin, and P. G. Johnston, "5-fluorouracil: mechanisms of action and clinical strategies," Nature reviews cancer, vol. 3, no. 5, pp. 330-338, 2003.
• C. Sethy and C. N. Kundu, "5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition," Biomedicine & Pharmacotherapy, vol. 137, p. 111285, 2021/05/01/ 2021, doi: 10.1016/j.biopha.2021.111285.
• T. C. Chou, "Frequently asked questions in drug combinations and the mass-action law-based answers," Synergy, vol. 1, no. 1, pp. 3-21, 2014/09/01/ 2014, doi: 10.1016/j.synres.2014.07.003.
• C. T. Keith, A. A. Borisy, and B. R. Stockwell, "Multicomponent therapeutics for networked systems," Nature Reviews Drug Discovery, vol. 4, no. 1, pp. 71-78, 2005/01/01 2005, doi: 10.1038/nrd1609.
• T. C. Chou, "The mass-action law based algorithms for quantitative econo-green bio-research," (in eng), Integr Biol (Camb), vol. 3, no. 5, pp. 548-59, May 2011, doi: 10.1039/c0ib00130a.
• N. Zhang, J. N. Fu, and T. C. Chou, "Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method," (in eng), Am J Cancer Res, vol. 6, no. 1, pp. 97-104, 2016.
• V. Banerjee et al., "Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method," (in eng), Eur J Pharmacol, vol. 897, p. 173919, Apr 15 2021, doi: 10.1016/j.ejphar.2021.173919.
• T. C. Chou, "The combination index (CI < 1) as the definition of synergism and of synergy claims," Synergy, vol. 7, pp. 49-50, 2018/12/01/ 2018, doi: 10.1016/j.synres.2018.04.001.
• D. A. Proia et al., "Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models," (in eng), Invest New Drugs, vol. 30, no. 6, pp. 2201-9, Dec 2012, doi: 10.1007/s10637-011-9790-6.
• S. Ohba, Y. Hirose, K. Yoshida, T. Yazaki, and T. Kawase, "Inhibition of 90-kD heat shock protein potentiates the cytotoxicity of chemotherapeutic agents in human glioma cells," (in eng), J Neurosurg, vol. 112, no. 1, pp. 33-42, Jan 2010, doi: 10.3171/2009.3.Jns081146.
• J. A. Friedman et al., "HSP90 Inhibitor SNX5422/2112 Targets the Dysregulated Signal and Transcription Factor Network and Malignant Phenotype of Head and Neck Squamous Cell Carcinoma," (in eng), Transl Oncol, vol. 6, no. 4, pp. 429-41, Aug 2013, doi: 10.1593/tlo.13292.
• Y. Liu et al., "Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells," (in eng), Int J Oncol, vol. 46, no. 1, pp. 299-307, Jan 2015, doi: 10.3892/ijo.2014.2714.