Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus

Author:

Silic-Benussi Micol1ORCID,Sharova Evgeniya1ORCID,Corradin Alberto1,Urso Loredana2,Raimondi Vittoria2ORCID,Cavallari Ilaria1,Buldini Barbara3,Francescato Samuela3,Minuzzo Sonia A.2ORCID,D’Agostino Donna M.14ORCID,Ciminale Vincenzo12

Affiliation:

1. Veneto Institute of Oncology IOV—IRCCS, 35128 Padova, Italy

2. Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy

3. Pediatric Hemato Oncology, Maternal and Child Health Department, University of Padova, 35128 Padova, Italy

4. Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy

Abstract

New therapies are needed for patients with T-cell lymphoblastic leukemia (T-ALL) who do not respond to standard chemotherapy. Our previous studies showed that the mTORC1 inhibitor everolimus increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis in T-ALL cells. Studies in T-ALL-xenografted NOD/SCID mice demonstrated that everolimus improved their response to the glucocorticoid (GC) dexamethasone. Here we show that verapamil, a calcium antagonist used in the treatment of supraventricular tachyarrhythmias, enhanced the effects of everolimus on ROS and cell death in T-ALL cell lines. The death-enhancing effect was synergistic and was confirmed in assays on a panel of therapy-resistant patient-derived xenografts (PDX) and primary samples from T-ALL patients. The verapamil-everolimus combination produced a dramatic reduction in the levels of G6PD and induction of p38 MAPK phosphorylation. Studies of NOD/SCID mice inoculated with refractory T-ALL PDX cells demonstrated that the addition of verapamil to everolimus plus dexamethasone significantly reduced tumor growth in vivo. Taken together, our results provide a rationale for repurposing verapamil in association with mTORC inhibitors and GC to treat refractory T-ALL.

Funder

Associazione Italiana per la Ricerca sul Cancro

University of Padova

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

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