Maize polyamine oxidase in the presence of spermine/spermidine induces the apoptosis of LoVo human colon adenocarcinoma cells

Ohkubo,Shinji; Mancinelli,Romina; Miglietta,Selenia; Cona,Alessandra; Angelini,Riccardo; Canettieri,Gianluca; Spandidos,Demetrios  A.; Gaudio,Eugenio; Agostinelli,Enzo

doi:10.3892/ijo.2019.4780

Maize polyamine oxidase in the presence of spermine/spermidine induces the apoptosis of LoVo human colon adenocarcinoma cells

Authors:
- Shinji Ohkubo
- Romina Mancinelli
- Selenia Miglietta
- Alessandra Cona
- Riccardo Angelini
- Gianluca Canettieri
- Demetrios A. Spandidos
- Eugenio Gaudio
- Enzo Agostinelli
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Affiliations: Department of Biochemical Sciences ‘A. Rossi Fanelli’, Sapienza University of Rome, I-00185 Rome, Italy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, I-00161 Rome, Italy, Department of Sciences, Roma Tre University, I-00146 Rome, Italy, Pasteur Laboratory, Department of Molecular Medicine, Sapienza University of Rome, I-00161 Rome, Italy, Laboratory of Clinical Virology, University of Crete School of Medicine, Heraklion 71003, Greece
Published online on: April 10, 2019 https://doi.org/10.3892/ijo.2019.4780
Pages: 2080-2094
Copyright: © Ohkubo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Amine oxidases, which contribute to the regulation of polyamine levels, catalyze the oxidative deamination of polyamines to generate H2O2 and aldehyde(s). In this study, and at least to the best of our knowledge, maize polyamine oxidase (ZmPAO) was used for the first time with the aim of identifying a novel strategy for cancer therapy. The cytotoxicity and the mechanisms of cell death induced by the enzymatic oxidation products of polyamine generated by ZmPAO were investigated. Exogenous spermine and ZmPAO treatment decreased cell viability in a spermine dose‑ and time‑dependent manner, particularly, the viability of the multidrug‑resistant (MDR) colon adenocarcinoma cells, LoVo DX, when compared with drug‑sensitive ones (LoVo WT). Further analyses revealed that H2O2 derived from spermine was mainly responsible for the cytotoxicity. Flow cytometric analysis revealed that treatment with ZmPAO and spermine increased the apoptotic population of LoVo WT and LoVo DX cells. In addition, we found that treatment with ZmPAO and spermine markedly reduced mitochondrial membrane potential in the LoVo DX cells, in agreement with the results of cell viability and apoptosis assays. Transmission electron microscopic observations supported the involvement of mitochondrial depolarization in the apoptotic process. Therefore, the dysregulation of polyamine metabolism in tumor cells may be a potential therapeutic target. In addition, the development of MDR tumor cells is recognized as a major obstacle in cancer therapy. Therefore, the design of a novel therapeutic strategy based on the use of this combination may be taken into account, making this approach attractive mainly in treating MDR cancer patients.

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