Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells

Abstract

Current chemotherapy for treatment of pediatric acute leukemia, although generally successful, is still a matter of concern due to treatment resistance, relapses and life-long side effects for a subset of patients. Inhibition of dynamin, a GTPase involved in clathrin-mediated endocytosis and regulation of the cell cycle, has been proposed as a potential anti-cancer regimen, but the effects of dynamin inhibition on leukemia cells has not been extensively addressed. Here we adopted single cell and whole-population analysis by flow cytometry and live imaging, to assess the effect of dynamin inhibition (Dynasore, Dyngo-4a, MitMAB) on pediatric acute leukemia cell lines (CCRF-CEM and THP-1), human bone marrow biopsies from patients diagnosed with acute lymphoblastic leukemia (ALL), as well as in a model of lymphoma (EL4)-induced tumor growth in mice. All inhibitors suppressed proliferation and induced pronounced caspase-dependent apoptotic cell death in CCRF-CEM and THP-1 cell lines. However, the inhibitors showed no effect on bone marrow biopsies, and did not prevent EL4-induced tumor formation in mice. We conclude that dynamin inhibition affects highly proliferating human leukemia cells. These findings form a basis for evaluation of the potential, and constraints, of employing dynamin inhibition in treatment strategies against leukemia and other malignancies.

Dental dilemmas in blood disorders: Navigating oral health in hematological diseases

“…Acute Lymphoblastic Leukemia (ALL) stands out as the most commonly diagnosed cancer in children, characterized by an aggressive growth of immature lymphocytes [10] . This disease accounts for 80% of all pediatric leukemias and 25% of all childhood cancers, making it the leading type of pediatric cancer [11] . In ALL, there is a marked increase in the production of blastocysts, immature cells in the bone marrow and blood.…”

The sulfonadyns: a class of aryl sulfonamides inhibiting dynamin I GTPase and clathrin mediated endocytosis are anti-seizure in animal models

“…33 Dynamin inhibition by Dyngo®-4a and MiTMAB causes death of leukemia and lymphoma cancer cells. 34 We have demonstrated that clinically used antipsychotic medications in the phenothiazine class, including the archetypical inhibitor chlorpromazine, are dynamin inhibitors. 35 In a human study the phenothiazine prochlorperazine reduces endocytosis in humans demonstrating that endocytosis inhibitor therapy is not inherently unsafe.…”

Prodrugs of the Archetypal Dynamin Inhibitor Bis‐T‐22

“… [27] In addition, dynamin inhibitors alter cell signalling pathways and have been shown to enhance the effects of existing chemotherapeutic approaches. [ 49 , 50 ] This suggests that targeting dynamin may be a novel anti‐cancer strategy. In support of this, dynole‐34‐2 and a phenothiazine drug were recently shown to be effective as combination therapies in mouse models of leukemia and head and neck cancer respectively,[ 49 , 51 ] or as a mono‐therapy in glioblastoma.…”