A clinically attainable dose of L‐asparaginase targets glutamine addiction in lymphoid cell lines

Abstract

L‐asparaginase (L‐ASNase) is an important branch of chemotherapy for acute lymphoblastic leukemia (ALL) and some types of non‐Hodgkin's lymphoma, including natural killer (NK)‐cell lymphoma. Although it mediates hydrolysis of asparagine (Asn) and glutamine (Gln), which are variably required for cancer cell survival, the relative contribution of Asn and Gln depletion to the anti‐tumor activity in therapeutic doses is unclear in ALL and malignant lymphoma. Here we demonstrate that L‐ASNase exerts cytotoxicity through targeting the Gln addiction phenotype in lymphoid cell lines. A clinically attainable intermediate dose of L‐ASNase induced massive apoptosis in ALL Jurkat and mantle cell lymphoma Jeko cell lines, while a low dose of L‐ASNase effectively killed NK‐cell lymphoma cells. In the lymphoid cell lines Jurkat and Jeco, deprivation of Gln but not Asn specifically suppressed cell growth and survival, and phenocopied the action of L‐ASNase. L‐ASNase treatment and Gln deprivation dramatically disrupted the refilling of the tricarboxylic acid (TCA) cycle by intracellular glutamate (Glu) and disturbed the mitochondrial integrity, which were alleviated by various anaplerotic TCA cycle intermediates, suggesting a direct contribution of glutaminase activity of L‐ASNase. The action of L‐ASNase differs between Jurkat cells and NK‐cell lymphoma cells, according to their dependence on Gln and Asn. Furthermore, we observed that high expression of glutaminase GLS1 is associated with increased sensivity to L‐ASNase in pediatric B lineage ALL. Our results redefine L‐ASNase as a therapeutic agent targeting Gln addiction in certain lymphoid cells and offer an additional basis for predicting L‐ASNase sensitivity and engineering selective L‐ASNase derivatives for leukemia and lymphoma.

Concurrent use of rabacfosadine and L‐asparaginase for relapsed or refractory multicentric lymphoma in dogs

“…L‐asparaginase (L‐ASP) is an enzyme commonly used in the treatment of lymphoma in dogs. It acts by depleting systemic asparagine/glutamine which leads to decreased capacity for protein synthesis and apoptosis of cells lacking asparagine synthetase, such as lymphocytes . Adverse events reported in dogs include hypersensitivity reactions, abnormal liver function tests, altered coagulation measurements, and pancreatitis .…”

“…It acts by depleting systemic asparagine/glutamine which leads to decreased capacity for protein synthesis and apoptosis of cells lacking asparagine synthetase, such as lymphocytes. 5,6 Adverse events reported in dogs include hypersensitivity reactions, abnormal liver function tests, altered coagulation measurements, and pancreatitis. 7 In humans, it is predominantly used in the treatment of acute lymphoblastic leukemia (ALL).…”

Genistein enhances the effects of L‐asparaginase on inducing cell apoptosis in human leukemia cancerHL‐60 cells

“…GEN showed apoptotic effects in a variety of cancer cell lines 9‐13 ; however, the study of GEN in human leukemia cancer HL‐60 cells 14,15 is still few and not fully understanding. Asp was used for chemotherapy to ALL and some types of non‐Hodgkin's lymphoma 18 . The effective approach of Asp was AIF‐mediated apoptosis 19 and it also induced cell autophagy in the treatment of AML 17,20 .…”

“…L‐asparaginase (Asp) catalyzes the degradation of L‐asparagine to form aspartic acid and ammonia 16 . Asp also upregulates glutamine synthase 17 and has been used for chemotherapy of ALL and some types of non‐Hodgkin's lymphoma 18 . Asp acts as a practical approach in treating AML via the AIF‐mediated apoptosis 19 .…”

Expressão da L-asparaginase II de >i<Saccharomyces cerevisiae>/i< recombinante extracelular com glicosilação humanizada em >i<Pichia pastoris>/i<

“…A ASNase também tem atividade glutaminásica, que é tema de debate na comunidade cientifica; discute-se se essa atividade também é essencial para a capacidade antileucêmica da enzima (PARMENTIER et al, 2015;SUGIMOTO et al, 2015;HUSAIN et al, 2016), incluindo efeito citotóxico para outros tipos de leucemia não linfoides (EMADI; ZOKAEE; SAUSVILLE, 2014).…”