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The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells

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Abstract

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC50 values for chlorpromazine and prazosin to have a molar range of 35–65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

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No datasets were generated or analysed during the current study.

References

  1. Li Q, Cao M, Lei L, Yang F, Li H, Yan X, He S, Zhang S, Teng Y, Xia C, Chen W. Burden of liver cancer: From epidemiology to prevention. Chin J Cancer Res. 2022;34(6):554–66. https://doi.org/10.21147/j.issn.1000-9604.2022.06.02.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tunissiolli N, Castanhole-Nunes M, Biselli-Chicote P, Pavarino É, Silva R, Silva R, Goloni-Bertollo E. Hepatocellular carcinoma: a comprehensive review of biomarkers, clinical aspects, and therapy. Asian Pac J Cancer Prev. 2017;18:863–72.

    PubMed  PubMed Central  Google Scholar 

  3. Golabi P, Fazel S, Otgonsuren M, Sayiner M, Locklear C, Younossi Z. Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities. Medicine (Baltimore). 2017. https://doi.org/10.1097/MD.0000000000005904.

    Article  PubMed  Google Scholar 

  4. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, Wang Q, Wang S, Rong D, Reiter F, Toni E, Wang X. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87. https://doi.org/10.1038/s41392-020-0187-x.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yang G, Xing J, Aikemu B, Jing S, Minhua Z. Kaempferol exhibits a synergistic effect with doxorubicin to inhibit proliferation, migration, and invasion of liver cancer. Oncol Rep. 2021;45:32. https://doi.org/10.3892/or.2021.7983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang Y, Zhang Y, Shi X, Li J, Wang L, Xie C, Wang Y. Chenodeoxycholic acid enhances the effect of sorafenib in inhibiting HepG2 cell growth through EGFR/Stat3 pathway. Front Oncol. 2022. https://doi.org/10.3389/fonc.2022.836333.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Erstad D, Tanabe K. Hepatocellular carcinoma: early-stage management challenges. J Hepatocell Carcinoma. 2017;4:81–92. https://doi.org/10.2147/JHC.S107370.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yang J, Hainaut P, Gores G, Amadou A, Plymoth A, Roberts L. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589–604. https://doi.org/10.1038/s41575-019-0186-y.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Silva M, Sherman M. Criteria for liver transplantation for HCC: what should the limits be? J Hepatol. 2011;55:1137–47. https://doi.org/10.1016/j.jhep.2011.05.012.

    Article  PubMed  Google Scholar 

  10. Chawla A, Ferrone C. Hepatocellular carcinoma surgical therapy perspectives on the current limits to resection. Chin Clin Oncol. 2018;7:48.

    Article  PubMed  Google Scholar 

  11. Zhang Z, Zhou L, Xie N, Edouard N, Zhang T, Cui Y, Huang C. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020;5:113. https://doi.org/10.1038/s41392-020-00213-8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lin S, Chueh S, Hsiao C, Li T, Chen T, Liao C, Lyu P, Guh J. Prazosin displays anticancer activity against human prostate cancers: targeting DNA and cell cycle. Neoplasia. 2007;9:830–9. https://doi.org/10.1593/neo.07475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kamgar-Dayhoff P, Brelidze T. Multifaceted effect of chlorpromazine in cancer implications for cancer treatment. Oncotarget. 2021;12:1406.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Papadopoulos F, Isihou R, Alexiou G, Tsalios T, Vartholomatos E, Markopoulos G, Sioka C, Tsekeris P, Kyritsis A, Galani V. Haloperidol induced cell cycle arrest and apoptosis in glioblastoma cells. Biomedicines. 2020;8:595. https://doi.org/10.3390/biomedicines8120595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. An M, Ma W, Jia H, Li Y, Feng J, Meng J, Hui Q, Liu J. Prazosin inhibits the growth and mobility of osteosarcoma cells. Transl Cancer Res. 2019;8:1997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xu F, Xi H, Liao M, Zhang Y, Ma H, Wu M, Xue Q, Sun H, Zhang Y, Xia Y. Repurposed antipsychotic chlorpromazine inhibits colorectal cancer and pulmonary metastasis by inducing G2/M cell cycle arrest, apoptosis, and autophagy. Cancer Chemother Pharmacol. 2022;89:331–46. https://doi.org/10.1007/s00280-021-04386-z.

    Article  CAS  PubMed  Google Scholar 

  17. Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29:347–64. https://doi.org/10.1038/s41422-019-0164-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pan F, Lin X, Hao L, Wang T, Song H, Wang R. The critical role of ferroptosis in hepatocellular carcinoma. Front Cell Dev Biol. 2022. https://doi.org/10.3389/fcell.2022.882571.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Poon I, Hulett M, Parish C. Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death Differ. 2010;17:381–97. https://doi.org/10.1038/cdd.2009.195.

    Article  CAS  PubMed  Google Scholar 

  20. Shlomovitz I, Speir M, Gerlic M. Flipping the dogma – phosphatidylserine in non-apoptotic cell death. Cell Commun Signal. 2019;17:139. https://doi.org/10.1186/s12964-019-0437-0.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Morgan K, Martucci N, Kozlowska A, et al. Chlorpromazine toxicity is associated with disruption of cell membrane integrity and initiation of a pro-inflammatory response in the HepaRG hepatic cell line. Biomed Pharmacother. 2019;111:1408–16. https://doi.org/10.1016/j.biopha.2019.01.020.

    Article  CAS  PubMed  Google Scholar 

  22. Fuchs R, Schwach G, Stracke A, et al. The anti-hypertensive drug prazosin induces apoptosis in the medullary thyroid carcinoma cell line TT. Anticancer Res. 2015;35(1):31–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lin SC, Chueh SC, Hsiao CJ, et al. Prazosin displays anticancer activity against human prostate cancers: targeting DNA and cell cycle. Neoplasia. 2007;9(10):830–9. https://doi.org/10.1593/neo.07475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rai S, Tanaka H, Suzuki M, et al. Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V. Nat Commun. 2020;11(1):4147. https://doi.org/10.1038/s41467-020-17666-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mann, S.K., Marwaha, R., Chlorpromazine. In: StatPearls. StatPearls Publishing; 2024. http://www.ncbi.nlm.nih.gov/books/NBK553079/

  26. Basquez, R., Pippin, M.M. Prazosin. In: StatPearls. StatPearls Publishing; 2024. http://www.ncbi.nlm.nih.gov/books/NBK555959/

  27. Fang J, Han T, Wu Q, Beland F, Chang C, Guo L, Fuscoe J. Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014;88:609–23. https://doi.org/10.1007/s00204-013-1169-3.

    Article  CAS  PubMed  Google Scholar 

  28. Li Y, Zuo H, Wang H, Hu A. Decrease of MLK4 prevents hepatocellular carcinoma (HCC) through reducing metastasis and inducing apoptosis regulated by ROS/MAPKs signaling. Biomed Pharmacother. 2019. https://doi.org/10.1016/j.biopha.2019.108749.

    Article  PubMed  Google Scholar 

  29. Srinivas U, Tan B, Vellayappan B, Jeyasekharan A. ROS and the DNA damage response in cancer. Redox Biol. 2019. https://doi.org/10.1016/j.redox.2018.101084.

    Article  PubMed  Google Scholar 

  30. Zhang, Y., Cao, Y., Luo, S., Mukerabigwi, J.F., Liu, M. Chapter 8 - Nanoparticles as drug delivery systems of combination therapy for cancer. In: Grumezescu AM, ed. Nanobiomaterials in Cancer Therapy. William Andrew Publishing, 2016, 253–280. doi:https://doi.org/10.1016/B978-0-323-42863-7.00008-6

  31. Yu B, Tai HC, Xue W, Lee LJ, Lee RJ. Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol. 2010;27(7):286–98. https://doi.org/10.3109/09687688.2010.521200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–92. https://doi.org/10.1200/JCO.2017.77.6112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Juaid N, Amin A, Abdalla A, et al. Anti-hepatocellular carcinoma biomolecules: molecular targets insights. Int J Mol Sci. 2021;22(19):10774. https://doi.org/10.3390/ijms221910774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Singh A, Mishra S, Sharma S, Ojha S, Yagnik S, Pandey S. Ligand-mediated targeted drug delivery approaches against hepatocellular carcinoma. Curr Cancer Drug Targets. 2023;23(11):879–88. https://doi.org/10.2174/1568009623666230503094346.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Missouri State University for the resources and materials provided within their facilities and laboratories.

Funding

This research was funded by Missouri State University Foundation Funds donated by the Nagarajan family.

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Author notes

  1. Seth Harris and Prithvi Nagarajan are first co-authors, equally contributed to the manuscript preparation.

Authors and Affiliations

  1. Department of Biology, Missouri State University, Springfield, MO, USA

    Seth Harris

  2. Thomas Jefferson Independent Day School, Joplin, MO, USA

    Prithvi Nagarajan & Kyoungtae Kim

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Contributions

Conceptualization, P.N and K.K; methodology, P.N, S.H, and K.K; software, P.N and S.H; validation, P.N, S.H, and K.K; formal analysis, P.N and S.H; investigation, P.N and S.H; resources, P.N and K.K; data curation, P.N and S.H; writing — original draft preparation, P.N; writing — review and editing, P.N, S.H, and K.K; visualization, P.N and S.H; supervision, K.K; project administration, K.K; funding acquisition, P.N and K.K. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Kyoungtae Kim.

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Harris, S., Nagarajan, P. & Kim, K. The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells. Med Oncol 41, 87 (2024). https://doi.org/10.1007/s12032-024-02323-7

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