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Enzymes in Metabolic Anticancer Therapy

  • Maristella MaggiEmail author
  • Claudia Scotti
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1148)

Abstract

Cancer treatment has greatly improved over the last 50 years, but it remains challenging in several cases. Useful therapeutic targets are normally unique peculiarities of cancer cells that distinguish them from normal cells and that can be tackled with appropriate drugs. It is now known that cell metabolism is rewired during tumorigenesis and metastasis as a consequence of oncogene activation and oncosuppressors inactivation, leading to a new cellular homeostasis typically directed towards anabolism. Because of these modifications, cells can become strongly or absolutely dependent on specific substrates, like sugars, lipids or amino acids. Cancer addictions are a relevant target for therapy, as removal of an essential substrate can lead to their selective cell-cycle arrest or even to cell death, leaving normal cells untouched. Enzymes can act as powerful agents in this respect, as demonstrated by asparaginase, which has been included in the treatment of Acute Lymphoblastic Leukemia for half a century. In this review, a short outline of cancer addictions will be provided, focusing on the main cancer amino acid dependencies described so far. Therapeutic enzymes which have been already experimented at the clinical level will be discussed, along with novel potential candidates that we propose as new promising molecules. The intrinsic limitations of their present molecular forms, along with molecular engineering solutions to explore, will also be presented.

Keywords

Cancer addictions Asparaginase Glutaminase Arginine deaminase Arginase 

Abbreviations

ADC

L-arginine decarboxylase

ADI

Arginine deiminase

AGA

Aspartylglucosaminidase

ALL

Acute lymphoblastic leukaemia

ARGase

L-Arginase

ASL

Argininosuccinate lyase

ASNase

Asparaginase

ASNS

Asparagine synthetase

AspATs

Aspartate aminotransferases

ASRLG1

β-aspartyl peptidase/L-asparaginase

ASS

Argininosuccinate synthase

ASS

Argininosuccinate synthetase

ATF4

Activating transcription factor 4

ATP

Adenosine triphosphate

BBB

Blood brain barrier

Bcl-2

B-cell lymphoma 2

BCT-100

Cysteines-mutated and PEGylated form of ARGase I

BFM

Berlin, Frankfurt, Münster

CGL

Cystathionine-γ-lyase

FAD

Flavin adenine dinucleotide

FAK

Focal adhesion kinase

GA

Glutaminase-asparaginase

GAC

Glutaminase C

GCS

Glycine cleavage system

GL

Bacterial glutaminase

GLS

Mammalian glutaminase

GO

Glycine oxidase

GRASPA

Erythrocytes encapsulating L-asparaginase

KGA

Kidney glutaminase

KRAS

Kirsten Rat sarcoma virus

Ma-ADI

Mycoplasma arginini derived ADI

MGL

L-methioninase

MTAP

Methylthioadenosine phosphorylase

mTORC1

Mammalian target of rapamycin complex 1

MTR

Methionine synthase

MYC and c-MYC

Myelocytomatosis gene

NADPH

Dihydronicotinamide-adenine dinucleotide Phosphate

NCI-60

National cancer institute-60 collection of cancer cell lines

Ntn

N-terminal nucleophile

OAT

Ornithine aminotransferase

OCT

Ornithine transcarbamyl transferase

P5C

Pyrroline-5-carboxylate

P5CS

Pyrroline-5-carboxylate synthase

PA

Plasminogen activator

PEG

Polyethylene glycole

PHGDH

Phosphoglycerate dehydrogenase

PIG-6

p53-induced gene 6

PLP

Pyrodoxal phosphate

PN

Pyridoxin

PpMGL

Pseudomonas putida L-methioninase

PRODH/POX

Proline oxidase

PSAT-1

Phosphoserine aminotransferase 1

PSPH

Phosphoserine phosphatase

PutA

Proline utilization A

PYCR1/2/L

Pyrroline-5-carboxylate reductase

Raf

Rapidly accelerated fibrosarcoma

Ras

Rat sarcoma

RBC

Red blood cell

RNAi

RNA interference

ROS

Radical oxygen species

RSV-BRL

Rous sarcoma virus-transformed buffalo-rat liver

SAM

S-adenosylmethionine

SC

Succinimidyl carbamate

SC-PEG

Calaspargase pegol

SDH

Serine dehydratase

SHMT

Serine hydroxymethyltransferase

TAT

L-tyrosine-2-oxoglutarate aminotransferase

TCA

Tricarboxylic acid cycle

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Molecular Medicine, Unit of Immunology and General PathologyUniversity of PaviaPaviaItaly

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