Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Abstract

L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.

<i>In vivo</i> stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

“…Unfortunately, these side effects prevent many patients from receiving their prescribed course of treatment, resulting in a detrimental impact on their outcome 50,51 . Several reports showed that the L-glutaminase co-activity of clinically used L-ASNases partially contributes to these unwanted side effects 21 . Therefore, lowering the L-glutaminase co-activity while maintaining its anti-cancer effect might provide the required safety profile that reduces treatment interruptions.…”

“…Because Gln levels are much higher, extensive ammonia levels are produced which might contribute to L-ASNase induced neurotoxicity [18][19][20] . The L-glutaminase co-activity also has an impact on protein synthesis in the liver and pancreas resulting in hepatotoxicity, pancreatitis, hyperglycemia, leukopenia and thrombosis 6,14,21 .…”

“…However, studies have shown that PEG itself can be immunogenic and that this anti-PEG immune response facilitates clearance in vivo 10,32,33 . Considering the bacterial origin of clinically used L-ASNases, immune responses against the enzyme itself are also commonly observed during therapy, including bronchospasms, anaphylactic shock, and hypersensitivity reactions 21,34,35 .…”

Asparagine, colorectal cancer, and the role of sex, genes, microbes, and diet: A narrative review

“…and Bacteroides caccae, Bifidobacterium dentium, and Blautia producta ., indicating that these bacteria used Asn as a growth source, and thus could affect Asn levels in the gut and perhaps of CRC patients. Whereas there are side effects associated with ASNase administration; E. coli ASNase can bind and inhibit the concanavalin A receptor, which accounts for non-immunological side effects and toxicities by ASNase ( Van Trimpont et al, 2022 ). Moreover, the Rhodospirillum rubrum mutant L-ASNase is unique to other bacterial ASNases as it can penetrate cancer cells via a clathrin receptor-dependent manner that suppressed telomerase activity and led to asparagine-independent cytotoxicity ( Zhdanov et al, 2017 ).…”

L-Asparaginase from Penicillium sizovae Produced by a Recombinant Komagataella phaffii Strain

“…Only asparaginase II is used for clinical application [11], and industrialized enzyme preparations are obtained from bacteria, such as the enzyme derived from E. coli in native and pegylated forms and the enzyme derived from Dickeya chrysanthemi (syn. Erwinia chrysanthemi) [12]. However, adverse effects such as hypersensitivity, coagulation disorders, pancreatitis, hyperglycaemia, hepatotoxicity and resistance to L-asparaginase with antibody formation in children with leukemia and lymphoma as well as in adults undergoing induction treatment for ALL when E. coli and D. chrysanthemi asparaginase were administered have been reported [13].…”