Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

Ramos-Acosta, Carlos; Huerta-Pantoja, Laura; Salazar-Hidalgo, Milton Eduardo; Mayol, Elsa; Jiménez-Vega, Selene; García-Peña, Pablo; Jordi-Cruz, Jenifeer; Baquero, Cristina; Porras, Almudena; Íñigo-Rodríguez, Belén; Benavente, Celina M.; López-Pastor, Andrea R.; Gómez-Delgado, Irene; Urcelay, Elena; Candel, Francisco Javier; Anguita, Eduardo

doi:10.3390/ijms25094887

Open AccessArticle

Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

by

Carlos Ramos-Acosta

^1,2,†,

Laura Huerta-Pantoja

^1,2,

Milton Eduardo Salazar-Hidalgo

²

,

Elsa Mayol

^1,2,

Selene Jiménez-Vega

^1,2

,

Pablo García-Peña

^1,2,

Jenifeer Jordi-Cruz

^1,2,

Cristina Baquero

³,

Almudena Porras

³

,

Belén Íñigo-Rodríguez

²,

Celina M. Benavente

^1,2,

Andrea R. López-Pastor

^4,5,

Irene Gómez-Delgado

^4,5

,

Elena Urcelay

^4,5

,

Francisco Javier Candel

^1,6 and

Eduardo Anguita

^1,2,*,†

¹

Department of Medicine, Medical School, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain

²

Hematology Department, IML, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Profesor Martín Lagos s/n, 28040 Madrid, Spain

³

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain

⁴

Laboratory of Genetics and Molecular Bases of Complex Diseases, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain

⁵

Networks for Cooperative Research in Health Results (RICORS, REI), 28089 Madrid, Spain

⁶

Clinical Microbiology & Infectious Diseases, Transplant Coordination, IML, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, 28040 Madrid, Spain

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2024, 25(9), 4887; https://doi.org/10.3390/ijms25094887

Submission received: 22 February 2024 / Revised: 23 April 2024 / Accepted: 27 April 2024 / Published: 30 April 2024

(This article belongs to the Special Issue Novel Therapeutics and Therapeutic Resistance in Hematological Malignancy)

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Abstract

Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.

Keywords: multiple myeloma; tigecycline; bortezomib; ROS; cell cycle; antagonism

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MDPI and ACS Style

Ramos-Acosta, C.; Huerta-Pantoja, L.; Salazar-Hidalgo, M.E.; Mayol, E.; Jiménez-Vega, S.; García-Peña, P.; Jordi-Cruz, J.; Baquero, C.; Porras, A.; Íñigo-Rodríguez, B.; et al. Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production. Int. J. Mol. Sci. 2024, 25, 4887. https://doi.org/10.3390/ijms25094887

AMA Style

Ramos-Acosta C, Huerta-Pantoja L, Salazar-Hidalgo ME, Mayol E, Jiménez-Vega S, García-Peña P, Jordi-Cruz J, Baquero C, Porras A, Íñigo-Rodríguez B, et al. Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production. International Journal of Molecular Sciences. 2024; 25(9):4887. https://doi.org/10.3390/ijms25094887

Chicago/Turabian Style

Ramos-Acosta, Carlos, Laura Huerta-Pantoja, Milton Eduardo Salazar-Hidalgo, Elsa Mayol, Selene Jiménez-Vega, Pablo García-Peña, Jenifeer Jordi-Cruz, Cristina Baquero, Almudena Porras, Belén Íñigo-Rodríguez, and et al. 2024. "Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production" International Journal of Molecular Sciences 25, no. 9: 4887. https://doi.org/10.3390/ijms25094887

APA Style

Ramos-Acosta, C., Huerta-Pantoja, L., Salazar-Hidalgo, M. E., Mayol, E., Jiménez-Vega, S., García-Peña, P., Jordi-Cruz, J., Baquero, C., Porras, A., Íñigo-Rodríguez, B., Benavente, C. M., López-Pastor, A. R., Gómez-Delgado, I., Urcelay, E., Candel, F. J., & Anguita, E. (2024). Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production. International Journal of Molecular Sciences, 25(9), 4887. https://doi.org/10.3390/ijms25094887

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Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

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