Skip to main content
SpringerLink
Log in

Molecular Cardiotoxic Effects of Proteasome Inhibitors Carfilzomib and Ixazomib and Their Combination with Dexamethasone Involve Mitochondrial Dysregulation

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

With the development and approval of new proteasome inhibitors, proteasome inhibition is increasingly recognized in cancer therapy. Besides successful anti-cancer effects in hematological cancers, side effects such as cardiotoxicity are limiting effective treatment. In this study, we used a cardiomyocyte model to investigate the molecular cardiotoxic mechanisms of carfilzomib (CFZ) and ixazomib (IXZ) alone or in combination with the immunomodulatory drug dexamethasone (DEX) which is frequently used in combination therapies in the clinic. According to our findings, CFZ showed a higher cytotoxic effect at lower concentrations than IXZ. DEX combination attenuated the cytotoxicity for both proteasome inhibitors. All drug treatments caused a marked increase in K48 ubiquitination. Both CFZ and IXZ caused an upregulation in cellular and endoplasmic reticulum stress protein (HSP90, HSP70, GRP94, and GRP78) levels and DEX combination attenuated the increased stress protein levels. Importantly, IXZ and IXZ-DEX treatments caused upregulation of mitochondria fission and fusion gene expression levels higher than caused by CFZ and CFZ-DEX combination. The IXZ-DEX combination reduced the levels of OXPHOS proteins (Complex II–V) more than the CFZ-DEX combination. Reduced mitochondrial membrane potential and ATP production were detected with all drug treatments in cardiomyocytes. Our findings suggest that the cardiotoxic effect of proteasome inhibitors may be due to their class effect and stress response and mitochondrial dysfunction may be involved in the cardiotoxicity process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Wu, P., Oren, O., Gertz, M. A., & Yang, E. H. (2020). Proteasome inhibitor-related cardiotoxicity: Mechanisms, diagnosis, and management. Current Oncology Reports, 22(7), 1–14.

    Article  Google Scholar 

  2. Shah, C., Bishnoi, R., Jain, A., Bejjanki, H., Xiong, S., Wang, Y., Zou, F., & Moreb, J. S. (2018). Cardiotoxicity associated with carfilzomib: Systematic review and meta-analysis. Leukemia & lymphoma, 59(11), 2557–2569.

    Article  CAS  Google Scholar 

  3. Jouni, H., Aubry, M. C., Lacy, M. Q., Kumar, S. K., Frye, R. L., & Herrmann, J. (2017). Ixazomib cardiotoxicity: A possible class effect of proteasome inhibitors. American Journal of Hematology, 92(2), 220–221.

    Article  CAS  PubMed  Google Scholar 

  4. Shirley, M. (2016). Ixazomib: First global approval. Drugs, 76(3), 405–411.

    Article  CAS  PubMed  Google Scholar 

  5. Ling, Y., Li, R., Zhong, J., Zhao, Y., & Chen, Z. (2022). Ixazomib-associated cardiovascular adverse events in multiple myeloma: A systematic review and meta-analysis. Drug and Chemical Toxicology, 45(4), 1443–1448.

    Article  CAS  PubMed  Google Scholar 

  6. Latif, A., Kapoor, V., Lateef, N., Ahsan, M. J., Usman, R. M., Malik, S. U., Ahmad, N., Rosko, N., Rudoni, J., William, P., Khouri, J., & Anwer, F. (2021). Incidence and management of carfilzomib-induced cardiovascular toxicity; A systematic review and meta-analysis. Cardiovascular & Haematological Disorders-Drug Targets (Formerly Current Drug Targets-Cardiovascular & Hematological Disorders), 21(1), 30–45.

    Article  CAS  Google Scholar 

  7. Dispenzieri, A., Kastritis, E., Wechalekar, A. D., Schönland, S. O., Kim, K., Sanchorawala, V., Landau, H. J., Kwok, F., Suzuki, K., Comenzo, R. L., Berg, D., Liu, G., Kumar, A., Faller, D. V., & Merlini, G. (2022). A randomized phase 3 study of ixazomib–dexamethasone versus physician’s choice in relapsed or refractory AL amyloidosis. Leukemia, 36(1), 225–235.

    Article  CAS  PubMed  Google Scholar 

  8. Das, A., Dasgupta, S., Gong, Y., Shah, U. A., Fradley, M. G., Cheng, R. K., Roy, B., & Guha, A. (2022). Cardiotoxicity as an adverse effect of immunomodulatory drugs and proteasome inhibitors in multiple myeloma: A network meta-analysis of randomized clinical trials. Hematological Oncology, 40(2), 233–242.

    Article  CAS  PubMed  Google Scholar 

  9. Varga, Z. V., Ferdinandy, P., Liaudet, L., & Pacher, P. (2015). Drug-induced mitochondrial dysfunction and cardiotoxicity. American Journal of Physiology-Heart and Circulatory Physiology, 309(9), H1453–H1467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gilda, J. E., & Gomes, A. V. (2017). Proteasome dysfunction in cardiomyopathies. The Journal of Physiology, 595(12), 4051–4071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Patel, M. B., & Majetschak, M. (2007). Distribution and interrelationship of ubiquitin proteasome pathway component activities and ubiquitin pools in various porcine tissues. Physiological Research, 56(3), 341–350.

    Article  CAS  PubMed  Google Scholar 

  12. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25(4), 402–408.

    Article  CAS  PubMed  Google Scholar 

  13. Wang, J., Fang, Y., Fan, R. A., & Kirk, C. J. (2021). Proteasome inhibitors and their pharmacokinetics, pharmacodynamics, and metabolism. International Journal of Molecular Sciences, 22(21), 11595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cole, D. C., & Frishman, W. H. (2018). Cardiovascular complications of proteasome inhibitors used in multiple myeloma. Cardiology in Review, 26(3), 122–129.

    Article  PubMed  Google Scholar 

  15. Grandin, E. W., Ky, B., Cornell, R. F., Carver, J., & Lenihan, D. J. (2015). Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. Journal of Cardiac Failure, 21(2), 138–144.

    Article  CAS  PubMed  Google Scholar 

  16. de Bruin, G., Xin, B. T., Kraus, M., van der Stelt, M., van der Marel, G. A., Kisselev, A. F., Driessen, C., Florea, B. I., & Overkleeft, H. S. (2016). A set of activity-based probes to visualize human (Immuno)proteasome activities. Angewandte Chemie International Edition, 55(13), 4199–4203. https://doi.org/10.1002/anie.201509092

    Article  CAS  PubMed  Google Scholar 

  17. Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., Jiang, J., Laidig, G. J., Lewis, E. R., Parlati, F., Shenk, K. D., Smyth, M. S., Sun, C. M., Vallone, M. K., Woo, T. M., Molineaux, C. J., & Bennett, M. K. (2007). Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Research, 67(13), 6383–6391. https://doi.org/10.1158/0008-5472.CAN-06-4086

    Article  CAS  PubMed  Google Scholar 

  18. Kupperman, E., Lee, E. C., Cao, Y., Bannerman, B., Fitzgerald, M., Berger, A., Yu, J., Yang, Y., Hales, P., Bruzzese, F., Liu, J., Blank, J., Garcia, K., Tsu, C., Dick, L., Fleming, P., Yu, L., Manfredi, M., Rolfe, M., & Bolen, J. (2010). Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Research, 70(5), 1970–1980.

    Article  CAS  PubMed  Google Scholar 

  19. Mendez-Lopez, M. A., Besse, A., Florea, B., Zuppinger, C., Overkleeft, H., Driessen, C., & Besse, L. (2019). Carfilzomib induces cardiotoxicity via ß5/ß2-specific proteasome subunit inhibition pattern. Blood, 134, 3110.

    Article  Google Scholar 

  20. Besse, A., Besse, L., Kraus, M., Mendez-Lopez, M., Bader, J., Xin, B. T., de Bruin, G., Maurits, E., Overkleeft, H. S., & Driessen, C. (2019). Proteasome inhibition in multiple myeloma: Head-to-head comparison of currently available proteasome inhibitors. Cell Chemical Biology, 26(3), 340–351.

    Article  CAS  PubMed  Google Scholar 

  21. Mateos, M. V., Goldschmidt, H., San-Miguel, J., Mikhael, J., DeCosta, L., Zhou, L., Obreja, M., Blaedel, J., Szabo, Z., & Leleu, X. (2018). Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: A subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials. Hematological Oncology, 36(2), 463–470.

    Article  CAS  PubMed  Google Scholar 

  22. Fradley, M. G., Groarke, J. D., Laubach, J., Alsina, M., Lenihan, D. J., Cornell, R. F., Maglio, M., Shain, K. H., Richardson, P. G., & Moslehi, J. (2018). Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma. British Journal of Haematology, 180(2), 271–275.

    Article  CAS  PubMed  Google Scholar 

  23. Moreau, P., Masszi, T., Grzasko, N., Bahlis, N. J., Hansson, M., Pour, L., Sandhu, I., Ganly, P., Baker, B. W., Jackson, S. R., Stoppa, A. M., Simpson, D. R., Gimsing, P., Palumbo, A., Garderet, L., Cavo, M., Kumar, S., Touzeau, C., Buadi, F. K., … TOURMALINE-MM1 Study Group. (2016). Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. New England Journal of Medicine, 374(17), 1621–1634.

    Article  CAS  PubMed  Google Scholar 

  24. Hasinoff, B. B., & Patel, D. (2018). Myocyte-damaging effects and binding kinetics of boronic acid and epoxyketone proteasomal-targeted drugs. Cardiovascular Toxicology. https://doi.org/10.1007/s12012-018-9468-9

    Article  PubMed  Google Scholar 

  25. Meyer, J. N., Leuthner, T. C., & Luz, A. L. (2017). Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology, 391, 42–53.

    Article  CAS  PubMed  Google Scholar 

  26. Nan, J., Zhu, W., Rahman, M. S., Liu, M., Li, D., Su, S., Zhang, N., Hu, X., Yu, H., Gupta, M. P., & Wang, J. (2017). Molecular regulation of mitochondrial dynamics in cardiac disease. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1864(7), 1260–1273.

    Article  CAS  PubMed  Google Scholar 

  27. Olmedo, I., Pino, G., Riquelme, J. A., Aranguiz, P., Díaz, M. C., López-Crisosto, C., Lavandero, S., Donoso, P., Pedrozo, Z., & Sánchez, G. (2020). Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1866(5), 165659.

    Article  CAS  PubMed  Google Scholar 

  28. Chen, I. C., Liu, Y. C., Wu, Y. H., Lo, S. H., Wang, S. C., Li, C. Y., Dai, Z. K., Hsu, J. H., Yeh, C. Y., & Tseng, Y. H. (2022). Proteasome inhibitors decrease the viability of pulmonary arterial smooth muscle cells by restoring mitofusin-2 expression under hypoxic conditions. Biomedicines, 10(4), 873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tibullo, D., Giallongo, C., Romano, A., Vicario, N., Barbato, A., Puglisi, F., Parenti, R., Amorini, A. M., Wissam Saab, M., Tavazzi, B., Mangione, R., Brundo, M. V., Lazzarino, G., Palumbo, G. A., Volti, G. L., Raimondo, F. D., & Lazzarino, G. (2020). Mitochondrial functions, energy metabolism and protein glycosylation are interconnected processes mediating resistance to bortezomib in multiple myeloma cells. Biomolecules, 10(5), 696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kolwicz, S. C., Jr., Purohit, S., & Tian, R. (2013). Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circulation Research, 113(5), 603–616.

    Article  CAS  PubMed  Google Scholar 

  31. Hoppins, S. (2014). The regulation of mitochondrial dynamics. Current Opinion in Cell Biology, 29, 46–52.

    Article  CAS  PubMed  Google Scholar 

  32. Chen, H., Vermulst, M., Wang, Y. E., Chomyn, A., Prolla, T. A., McCaffery, J. M., & Chan, D. C. (2010). Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell, 141(2), 280–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Forghani, P., Rashid, A., Sun, F., Liu, R., Li, D., Lee, M. R., Hwang, H., Maxwell, J. T., Mandawat, A., Wu, R., Salaita, K., & Xu, C. (2021). Carfilzomib treatment causes molecular and functional alterations of human induced pluripotent stem cell-derived cardiomyocytes. Journal of the American Heart Association, 10(24), e022247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stahn, C., & Buttgereit, F. (2008). Genomic and nongenomic effects of glucocorticoids. Nature Clinical Practice Rheumatology, 4(10), 525–533.

    Article  CAS  PubMed  Google Scholar 

  35. Desquiret, V., Gueguen, N., Malthièry, Y., Ritz, P., & Simard, G. (2008). Mitochondrial effects of dexamethasone imply both membrane and cytosolic-initiated pathways in HepG2 cells. The International Journal of Biochemistry & Cell Biology, 40(8), 1629–1641.

    Article  CAS  Google Scholar 

  36. Troncoso, R., Paredes, F., Parra, V., Gatica, D., Vásquez-Trincado, C., Quiroga, C., Bravo-Sagua, R., López-Crisosto, C., Rodriguez, A. E., Oyarzún, A. P., Kroemer, G., & Lavandero, S. (2014). Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance. Cell Cycle, 13(14), 2281–2295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou, R., Li, J., Zhang, L., Cheng, Y., Yan, J., Sun, Y., Wang, J., & Jiang, H. (2020). Role of Parkin-mediated mitophagy in glucocorticoid-induced cardiomyocyte maturation. Life Sciences, 255, 117817.

    Article  CAS  PubMed  Google Scholar 

  38. Rajashree, S., & Puvanakrishnan, R. (1998). Dexamethasone induced alterations in enzymatic and nonenzymatic antioxidant status in heart and kidney of rats. Molecular and Cellular Biochemistry, 181(1), 77–85.

    Article  CAS  PubMed  Google Scholar 

  39. Karademir, B., Sari, G., Jannuzzi, A. T., Musunuri, S., Wicher, G., Grune, T., Mi, J., Hacioglu-Bay, H., Forsberg-Nilsson, K., Bergquist, J., & Jung, T. (2018). Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib. Scientific Reports, 8(1), 16318.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Jannuzzi, A. T., Arslan, S., Yilmaz, A. M., Sari, G., Beklen, H., Méndez, L., Fedorova, M., Arga, K. Y., Karademir Yilmaz, B., & Alpertunga, B. (2020). Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib. Redox Biology, 32, 101502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study is supported by Istanbul University Research Fund. (Grant No: TSA-2019–33638).

Author information

Author notes

  1. Buket Alpertunga

    Present address: Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul Health and Technology University, Istanbul, Turkey

Authors and Affiliations

  1. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

    Ayse Tarbin Jannuzzi & Buket Alpertunga

  2. Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey

    Nalan Sümeyra Korkmaz, Sema Arslan Eseryel & Betul Karademir Yilmaz

  3. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey

    Aysenur Gunaydin Akyildiz

Authors
  1. Ayse Tarbin Jannuzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nalan Sümeyra Korkmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aysenur Gunaydin Akyildiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sema Arslan Eseryel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Betul Karademir Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Buket Alpertunga
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ATJ, BKY, and BA designed the experiments. ATJ, NSK, AGA, and SAE performed the experiments and analyzed the data. ATJ wrote the manuscript. All of the authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Ayse Tarbin Jannuzzi.

Ethics declarations

Competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Handling Editor: Kumuda Das.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jannuzzi, A.T., Korkmaz, N.S., Gunaydin Akyildiz, A. et al. Molecular Cardiotoxic Effects of Proteasome Inhibitors Carfilzomib and Ixazomib and Their Combination with Dexamethasone Involve Mitochondrial Dysregulation. Cardiovasc Toxicol 23, 121–131 (2023). https://doi.org/10.1007/s12012-023-09785-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-023-09785-7

Keywords

Search

Navigation