Evaluation of Potential Hepatotoxicity Induced by Bortezomib

Duygu Mutluay, Yanad Abou Monsef, Gözde Yücel Tenekeci

Abstract


Background: Bortezomib, an inhibitor of 26S proteasome, is an anti-cancer therapeutic agent used in different cancer types. It leads to the arrest of the cancerous cell cycle by inhibiting angiogenesis and inducing apoptosis. Liver is the vital organ for detoxification and excretion of toxic products. The treatment with chemotherapy is a challenge, drugs are used to destroy cancer cells, but healthy cells can be affected during cancer treatment as well. The main objective of this study was to analyze the histopathological and biochemical effects of bortezomib on liver.

Materials, Methods & Results: Twenty-four female C57BL/6 mice were distributed into 4 groups, bortezomib injected treatment groups (Btz1, Btz2) and saline injected control groups (C1, C2). Bortezomib and saline treated twice per week for 6 weeks and sacrificed at the end of one day (Btz1, C1) and 4 weeks (Btz2, C2) after the last injection. Liver samples were examined for histopathological analysis and the serum samples processed for biochemical analysis. Tissue samples were fixed, routinely processed, sectioned, and stained with Hematoxylin and Eosin (H&E). Periodic Acid-Schiff (PAS), Sudan Black staining and Masson's trichrome histochemical staining methods were performed to characterize the lesions. Histopathological analysis of the Btz1 and Btz2 groups revealed acute hepatic morphological changes such as hepatocellular swelling (cloudy swelling), necro-inflammatory reaction, and increased mononuclear polyploidy. Based on the negative staining with PAS and Sudan Black staining, hepatocellular swelling was diagnosed as hydropic degeneration. Necro-inflammatory reaction observed in the form of acute hepatitis was composed of mainly mononuclear cell infiltration accompanied by multifocal necrotic foci. Kupffer cell proliferation was observed in parallel with degenerative and necrotic changes. An Increase in hepatocellular mononuclear polyploidy visualized as hepatocytes with a single enlarged nucleus was detected in all liver sections of Btz1 and Btz2 groups Individual cases of cholestasis (n = 1) and mild hepatic fibrosis (n = 1) were also reported. Significant elevated levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were detected in bortezomib treated groups.

Discussion: Few clinical casesreported liver injury related to bortezomib used for cancer treatment. However, the liver was not considered as a target for bortezomib treatment. Our data suggesting that bortezomib caused liver damage and induce elevations in serum levels. The reported hepatic lesions including hepatocellular swelling, acute hepatitis and mononuclear polyploidy were mainly mild and moderate in severity. The increase of polyploidy in liver tissue of mice treated with bortezomib in this study was explained as a reaction of the liver facing the drug-induced hepatic damage. The mechanism leading to the hepatotoxicity of bortezomib treatment is not known but the production of a toxic metabolite through its metabolism in the liver can be suggested. Moreover, no recovery was also observed in histopathological and biochemical analyses suggesting that the bortezomib effect is non-reversible four weeks after the drug was withdrawn. Patients should be informed about the possibility of acute drug-induced hepatitis and hepatotoxicity of this chemotherapeutic agent after the treatment.

Keywords: bortezomib, cancer, chemotherapy, hepatotoxicity, liver, proteasome inhibitor.


Full Text:

PDF

References


Araujo K.P., Bonuccelli G., Duarte C. N., Gaiad T.P., Moreira D.F., Feder D., Belizario J.E., Miglino M.A. Lisanti M.P. & Ambrosio C.E. 2013. Bortezomib (PS-341) treatment decreases inflammation and partially rescues the expression of the dystrophin-glycoprotein complex in GRMD dogs. PloS One. 8(4): e61367.

Blouin J.M., Duchartre Y., Costet P., Lalanne M., Ged C., Lain A., Millet O., de Verneuil H. & Richard E. 2013. Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria. Proceedings of the National Academy of Sciences (Proceedings of the National Academy of Sciences of the United States of America). 110: 18238-18243.

Brignole, C., Marimpietri D., Pastorino F, Nico B., Di Paolo D., Cioni M., Piccardi F, Cilli M., Pezzolo A., Corrias M.V., Pistoia V., Ribatti D., Pagnan G. & Ponzoni M. 2006. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. Journal of the National Cancer Institute. 98(16): 1142-1157.

Bruna J., Udina E., Alé A., Vilches J.J., Vynckier A., Monbaliu J., Silverman L. & Navarro X. 2010. Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice. Experimental Neurology. 223(2): 599-608.

Dick L.R. & Fleming P.E. 2010. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discovery Today. 15(5-6): 243-249.

Dobson J.M. 2013. Breed-predispositions to cancer in pedigree dogs. International Scholarly Research Network Veterinary Science. 2013(11): DOI 10.1155/2013/941275

El-Sayyad H.I., Ismail M.F., Shalaby F.M., Abou-El-Magd R.F., Gaur R.L., Fernando A., Raj M.H. & Ouhtit A. 2009. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. International Journal of Biological Sciences. 28(5): 466-473.

Everds N.E. 2015. Evaluation of clinical pathology data: correlating changes with other study data. Toxicologic pathology. 43(1): 90-97.

Hasan K.M.M., Tamanna N. & Haque M.A. 2018. Biochemical and histopathological profiling of Wistar rat treated with Brassica napus as a supplementary feed. Food science and human wellness. 7(1): 77-82.

Ito K., Kobayashi M., Kuroki S., Sasaki Y., Iwata T., Mori K., Kuroki T., Ozawa Y., Tetsuka M., Nakagawa T., Hiroi T., Yamamoto H., Ono K., Washizu T. & Bonkobara M. 2013. The proteasome inhibitor bortezomib inhibits the growth of canine malignant melanoma cells in vitro and in vivo. The Veterinary Journal. 198(3): 577-82.

Iwamoto T., Ishibashi M., Fujieda A., Masuya M., Katayama N. & Okuda M. 2010. Drug interaction between itraconazole and bortezomib: exacerbation of peripheral neuropathy and thrombocytopenia induced by bortezomib. Pharmacotherapy. 30(7): 661-665.

Jackson G., Einsele H., Moreau P. & Miguel J.S. 2005. Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies. Cancer Treatment Reviews. 31: 591-602.

Jain A., Malhotra P., Suri V., Varma S., Das A. & Mitra S. 2016. Cholestasis in a Patient of Multiple Myeloma: A Rare Occurrence of Bortezomib Induced Liver Injury. Indian Journal of Hematology and Blood Transfusion. 32(1): 181-183.

Kim Y., Kim K.Y., Lee S.H., Chung Y.Y., Yahng S.A., Lee S.E., Park G. & Min C.K. 2012. A Case of Drug-Induced Hepatitis due to Bortezomib in Multiple Myeloma. Immune Network. 12(3): 126-128.

Kreutz C., MacNelly S., Follo M., Wäldin A., Binninger-Lacour P., Timmer J. & Bartolomé-Rodríguez M.M. 2017. Hepatocyte ploidy is a diversity factor for liver homeostasis. Frontiers in physiology. 8: 862.

Li Z., Wu Q., Yan Z., Li D., Lu G., Mou W., Wu S., Pan X., Lu Q. & Xu K. 2013. The protection and therapy effects of bortezomib in murine acute graft-versus-host disease. Transplantation Proceedings. 45: 2527-2535.

Liang W., Menke A.L., Driessen A., Koek G.H., Lindeman J.H., Stoop R., Havekes L.M., Kleemann R. & Van den Hoek A.M. 2014. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PloS one. 9(12): e115922.

LiverTox. 2012. Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases - Bortezomib. [Updated 2017 Sep 30]. Available at https://www.ncbi.nlm.nih.gov/books/

Ludwig H., Khayat D., Giaccone G. & Facon T. 2005. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer. 104: 1794-1807.

Luna L.G. 1968. Manual of Histological Staining Methods of the Armed Forces Institute of Pathology. 3rd edn. New York: McGraw Hill Book Company,186p.

Monahan P.E., Lothrop C.D., Sun J., Hirsch M.L., Kafri T., Kantor B., Sarkar R., Tillson D.M., Elia J.R. & Samulski R.J. 2010. Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application. Molecular therapy: the journal of the American Society of Gene Therapy. 18(11): 1907-1916.

Patatsos K., Shekhar T.M. & Hawkins C.J. 2018. Pre-clinical evaluation of proteasome inhibitors for canine and human osteosarcoma. Veterinary and Comparative Oncology. 16(4): 544-553.

Ramadori G. & Cameron S. 2010. Effects of systemic chemotherapy on the liver. Annals of Hepatology. 9(2): 133-143.

Rao S.R., Somarelli J.A., Altunel E., Selmic L.E., Byrum M., Sheth M.U., Cheng S., Ware K.E., Kim S.Y., Prinz J.A., Devos N., Corcoran D.L., Moseley A., Soderblom E., Hsu S.D. & Eward W.C. 2020. From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine. Frontiers in Oncology. 10: 117.

Reagan-Shaw S., Nihal M. & Ahmad N. 2008. Dose translation from animal to human studies revisited. Federation of American Societies for Experimental Journal. 22(3): 659-661.

Rochette L., Guenancia C., Gudjoncik A., Hachet O., Zeller M., Cottin Y. & Vergely C. 2015. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends in Pharmacological Sciences. 36: 326-348.

Rosiñol L., Montoto S., Cibeira M.T. & Bladé J. 2005. Bortezomib-induced severe hepatitis in multiple myeloma: a case report. Archives of Internal Medicine. 165(4): 464-465.

Sato H., Matsuda K., Amagai Y., Tanaka A. & Matsuda H. 2018. Suppressive Effect of Bortezomib on LPS-Induced Inflammatory Responses in Horses. Journal of Equine Veterinary Science. 61: 114-120.

Toyoda H., Bregerie O., Vallet A., Nalpas B., Pivert G., Brechot C. & Desdouets C. 2005. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis. Gut. 54(2): 297-302.

Trevisan G., Materazzi S., Fusi C., Altomare A., Aldini G., Lodovici M., Patacchini R., Geppetti P. & Nassini R. 2013. Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Research. 73(10): 3120-3131.

Voorhees P.M., Dees E.C., O'Neil B. & Orlowski R.Z. 2003. The proteasome as a target for cancer therapy. Clinical Cancer Research. 9: 6316-6325.

Yu X., Huang S., Patterson E., Garrett M.W., Kaufman K.M., Metcalf J.P., Zhu M., Dunn S.T. & Kem D.C. 2005. Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction. American journal of physiology. Heart and circulatory physiology. 289(5): H1960-H1967.




DOI: https://doi.org/10.22456/1679-9216.116456

Copyright (c) 2021 Duygu Mutluay

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.