Autophagy activation can partially rescue proteasome dysfunction-mediated cardiac toxicity.

The ubiquitin-proteasome pathway and its functional interplay with other proteostatic and/or mitostatic modules are crucial for cell viability, especially in post-mitotic cells like cardiomyocytes, which are constantly exposed to proteotoxic, metabolic, and mechanical stress. Consistently, treatment of multiple myeloma patients with therapeutic proteasome inhibitors may induce cardiac failure; yet the effects promoted by heart-targeted proteasome dysfunction are not completely understood. We report here that heart-targeted proteasome knockdown in the fly experimental model results in increased proteome instability and defective mitostasis, leading to disrupted cardiac activity, systemic toxicity, and reduced longevity. These phenotypes were partially rescued by either heart targeted- or by dietary restriction-mediated activation of autophagy. Supportively, activation of autophagy by Rapamycin or Metformin administration in flies treated with proteasome inhibitors reduced proteome instability, partially restored mitochondrial function, mitigated cardiotoxicity, and improved flies' longevity. These findings suggest that autophagic inducers represent a novel promising intervention against proteasome inhibitor-induced cardiovascular complications

Differential donor-, cell type- and drug-specific molecular responses to therapeutic proteasome inhibitors in Multiple Myeloma patients and cells

Purpose of the study: Proteasome over‐activation represents a hallmark of several advanced tumors and thus, its selective inhibition provides a promising anti‐tumor therapy. Consistently, proteasome inhibitors (PIs) have demonstrated clinical efficacy in the treatment of multiple myeloma (MM) and mantle cell lymphoma and are evaluated for the treatment of other malignancies. Herein we analyzed the molecular responses induced in red blood‐ (RBCs) cells and peripheral blood mononucleated‐ (PBMCs) cells of MM patients treated with therapeutic PIs; given also that disease relapse usually refers to MM cells that survive therapy, we also investigated the molecular responses induced in MM cells after non‐lethal proteasome inhibition.Bio-organic Synthesi

Elucidating carfilzomib’s induced cardiotoxicity in an in vivo model of aging: Prophylactic potential of metformin

Background: Carfilzomib is a first‐line proteasome inhibitor indicated for relapsed/refractory multiple myeloma (MM), with its clinical use being hampered by cardiotoxic phenomena. We have previously established a translational model of carfilzomib cardiotoxicity in young adult mice, in which metformin emerged as a prophylactic therapy. Considering that MM is an elderly disease and that age is an independent risk factor for cardiotoxicity, herein, we sought to validate carfilzomib’s cardiotoxicity in an in vivo model of aging. Methods: Aged mice underwent the translational two‐ and four‐dose protocols without and with metformin. Mice underwent echocardiography and were subsequently sacrificed for molecular analyses in the blood and cardiac tissue. Results: Carfilzomib decreased proteasomal activity both in PBMCs and myocardium in both proto-cols. Carfilzomib induced mild cardiotoxicity after two doses and more pronounced cardiomyopathy in the four‐dose protocol, while metformin maintained cardiac function. Carfilzomib led to an increased Bip expression and decreased AMPKα phosphorylation, while metformin coadministration partially decreased Bip expression and induced AMPKα phosphorylation, leading to enhanced myocardial LC3B‐dependent autophagy. Conclusion: Carfilzomib induced cardiotoxicity in aged mice, an effect significantly reversed by metformin. The latter possesses translational importance as it further supports the clinical use of metformin as a potent prophylactic therapy. © 2021 by the authors. Licensee MDPI, Basel, Switzerland