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Molecular mechanisms of Carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of Metformin

Panagiotis Efentakis, Georgios Kremastiotis, Aimilia Varela, Panagiota-Efstathia Nikolaou, Eleni-Dimitra Papanagnou, Constantinos H. Davos, Maria Tsoumani, Georgios Agrogiannis, Anastasia Konstantinidou, Efstathios Kastritis, Zoi Kanaki, Efstathios K. Iliodromitis, Apostolos Klinakis, Meletios A. Dimopoulos, Ioannis P. Trougakos, Ioanna Andreadou and Evangelos Terpos

Key points

  • Cfz decreases left ventricular function in mice through increased PP2A activity and inhibition of AMPKα/ autophagy regulatory axes.

  • Metformin preserves left ventricular function in mice, by restoring AMPKα activation; thus, it emerges as a prophylactic therapy.

Abstract

Carfilzomib (Cfz), an irreversible proteasome inhibitor licensed for relapsed/refractory myeloma, is associated with cardiotoxicity in humans. We sought to establish the optimal protocol of Cfz-induced cardiac dysfunction, to investigate the underlying molecular-signaling and based on the findings, to evaluate the cardioprotective potency of Metformin (Met). Mice were randomized into: Protocols 1 and 2 (Control and Cfz for 1 and 2 consecutive days, respectively); Protocols 3 and 4 (Control and alternate doses of Cfz for 6 and 14 days, respectively); Protocols 5 A, B (Control and Cfz, intermittent doses on days 0, 1 and 7, 8 for 13 days); Protocols 6 A, B (pharmacological intervention; Control, Cfz, Cfz+Met and Met for 2 and 6 days, respectively) and Protocol 7 (bortezomib). Cfz was administered at 8 mg/kg(ip) and Met at 140 mg/kg(po). Cfz resulted in significant reduction of proteasomal activity in heart and PBMCs in all protocols except protocols 5. Echocardiography demonstrated that Cfz led to a significant fractional shortening (FS) depression in protocols 2 and 3, a borderline dysfunction in protocols 1 and 4 and had no detrimental effect on protocols 5. Molecular analysis revealed that Cfz inhibited AMPKα/mTORC1 pathways derived from increased PP2A activity in Protocol 2, whereas it additionally inhibited PI3K/Akt/eNOS pathway in Protocol 3. Co-administration of Met prevented Cfz-induced FS reduction and restored AMPKα phosphorylation and autophagic signaling. Conclusively, Cfz decreased left ventricular function through increased PP2A activity and inhibition of AMPKα and its downstream autophagic targets, while Met represents a novel promising intervention against Cfz-induced cardiotoxicity.

  • Submitted June 18, 2018.
  • Accepted November 9, 2018.