Top

Published in:

21-02-2023 | Dexamethasone

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

Authors: Ayse Tarbin Jannuzzi, Nalan Sümeyra Korkmaz, Aysenur Gunaydin Akyildiz, Sema Arslan Eseryel, Betul Karademir Yilmaz, Buket Alpertunga

Published in: Cardiovascular Toxicology | Issue 3-4/2023

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.

Available only for authorised users

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.CrossRef

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.CrossRef

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.CrossRefPubMed

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

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

10.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

14.

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

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.CrossRefPubMed

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.201509092CrossRefPubMed

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-06-4086CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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/s12012-018-9468-9CrossRefPubMed

25.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

31.

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

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

34.

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

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

Title: Molecular Cardiotoxic Effects of Proteasome Inhibitors Carfilzomib and Ixazomib and Their Combination with Dexamethasone Involve Mitochondrial Dysregulation
Authors: Ayse Tarbin Jannuzzi
Nalan Sümeyra Korkmaz
Aysenur Gunaydin Akyildiz
Sema Arslan Eseryel
Betul Karademir Yilmaz
Buket Alpertunga
Publication date: 21-02-2023
Publisher: Springer US
Keyword: Dexamethasone
Published in: Cardiovascular Toxicology / Issue 3-4/2023
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-023-09785-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3-4/2023

Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway

Retraction Note: Dapagliflozin Guards Against Cadmium-Induced Cardiotoxicity via Modulation of IL6/STAT3 and TLR2/TNFα Signaling Pathways

Cardiac Effects of Micrurus corallinus and Micrurus dumerilii carinicauda (Elapidae) Venoms and Neutralization by Brazilian Coralsnake Antivenom and Varespladib

Nogo-A Mediated Endoplasmic Reticulum Stress During Myocardial Ischemic-Reperfusion Injury in Diabetic Rats