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Article

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma

1
H12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, Spain
2
Hematology Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
3
Pathology Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
4
CNIO–Lilly Cell Signalling and Immunometabolism Section, CNIO, 28029 Madrid, Spain
5
Biochemistry and Molecular Biology Department, Pharmacy School, Universidad Complutense de Madrid, 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
Contributed equally as co-first authors.
Contributed equally as co-senior authors.
Academic Editor: Aldo M. Roccaro
Cancers 2021, 13(7), 1662; https://doi.org/10.3390/cancers13071662
Received: 28 February 2021 / Revised: 25 March 2021 / Accepted: 29 March 2021 / Published: 1 April 2021
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
Multiple myeloma represents the cancer with the 21st highest global incidence. The rapid acquisition of drug resistance to proteasome inhibitors requires a deep knowledge on the mechanisms involved in proliferation in order to provide novel targets for the disease. The aim of our study was to characterize the mitochondrial activity in primary multiple myeloma (MM) cells along the course of the disease and to provide a therapeutic alternative to inhibit Myc function by blocking OXPHOS metabolism. We confirmed MM patients show enhanced mitochondrial activity linked to c-Myc expression. The use of tigecycline provides evidence for a novel strategy addressing c-Myc functionality by mitochondrial activity inhibition.
Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities. View Full-Text
Keywords: multiple myeloma; mitochondria; tigecycline; MYC multiple myeloma; mitochondria; tigecycline; MYC
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MDPI and ACS Style

Ortiz-Ruiz, A.; Ruiz-Heredia, Y.; Morales, M.L.; Aguilar-Garrido, P.; García-Ortiz, A.; Valeri, A.; Bárcena, C.; García-Martin, R.M.; Garrido, V.; Moreno, L.; Gimenez, A.; Navarro-Aguadero, M.Á.; Velasco-Estevez, M.; Lospitao, E.; Cedena, M.T.; Barrio, S.; Martínez-López, J.; Linares, M.; Gallardo, M. Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma. Cancers 2021, 13, 1662. https://doi.org/10.3390/cancers13071662

AMA Style

Ortiz-Ruiz A, Ruiz-Heredia Y, Morales ML, Aguilar-Garrido P, García-Ortiz A, Valeri A, Bárcena C, García-Martin RM, Garrido V, Moreno L, Gimenez A, Navarro-Aguadero MÁ, Velasco-Estevez M, Lospitao E, Cedena MT, Barrio S, Martínez-López J, Linares M, Gallardo M. Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma. Cancers. 2021; 13(7):1662. https://doi.org/10.3390/cancers13071662

Chicago/Turabian Style

Ortiz-Ruiz, Alejandra, Yanira Ruiz-Heredia, María L. Morales, Pedro Aguilar-Garrido, Almudena García-Ortiz, Antonio Valeri, Carmen Bárcena, Rosa M. García-Martin, Vanesa Garrido, Laura Moreno, Alicia Gimenez, Miguel Á. Navarro-Aguadero, María Velasco-Estevez, Eva Lospitao, María T. Cedena, Santiago Barrio, Joaquín Martínez-López, María Linares, and Miguel Gallardo. 2021. "Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma" Cancers 13, no. 7: 1662. https://doi.org/10.3390/cancers13071662

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