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Anticancer drugs and hyperthermia enhance cytotoxicity induced by polyamine enzymatic oxidation products

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Summary.

A correlation between regulation of cell proliferation and polyamine metabolism is described. The latter can enter protein synthesis through the modification of eukaryotic initiation factor 5A (eIF5A) and the formation of the peculiar amino acid hypusine. Specific inhibitors of hypusine formation induce apoptosis that can be potentiated by the combination with cytokines such as interferonα (IFNα) that itself decreases hypusine synthesis. We have also demonstrated that the concomitant treatment of cancer cells with IFNα and the protein synthesis inhibitor fusion protein TGFα/Pseudomonas Aeruginosa toxin synergize in inducing cancer cell growth inhibition. Another way used by polyamines to induce apoptosis is the generation of intracellular oxidative stress through the interaction with bovine serum amine oxidase (BSAO). This enzyme used simultaneously to spermine induces apoptosis, necrosis, inhibition of cell proliferation and inhibition of DNA and protein synthesis in several cell types. The enzymatic oxidation products of polyamine, H2O2 and aldehyde(s) cause these effects. We have recently found that the cytotoxicity of anti-cancer agents, either etoposide or docetaxel, in cancer cells is potentiated in the presence of BSAO/Spermine. In conclusion, polyamine metabolites could be useful in the design of new therapeutic strategies.

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Abbreviations

AO:

amine oxidase

BSA:

bovine serum albumin

BSAO:

bovine serum amine oxidase

CHO:

chinese hamster ovary

cyclin/cdks:

cyclin-dependent kinase

DFMO:

2-(difluoromethyl)ornithine

DTX:

docetaxel

EGF-R:

epidermal growth factor receptor

eIF5A:

eukaryotic initiation factor 5A

HTC:

hepatoma tissue culture

IFNα:

interferon alpha

MDL 72527:

N1,N4-bis(2,3-butadienyl)-1,4-butanediamine

MDR:

multidrug resistance

ODC:

ornithine decarboxylase

PAO:

polyamine oxidase

PEG:

poly ethylene glycol

Put:

putrescine

ROS:

reactive oxygen species

SAMDC:

S-adenosylmethionine decarboxylase

SAO:

serum amine oxidase

Spd:

spermidine

Spm:

spermine

SSAT:

spermidine/spermine N 1-acetyltransferase

VP16:

etoposide

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Marra, M., Agostinelli, E., Tempera, G. et al. Anticancer drugs and hyperthermia enhance cytotoxicity induced by polyamine enzymatic oxidation products. Amino Acids 33, 273–281 (2007). https://doi.org/10.1007/s00726-007-0536-x

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