Sensitization of human colon adenocarcinoma cells (LoVo) to reactive oxygen species by a lysosomotropic compound

Agostinelli, Enzo; Vedova, Laura Dalla; Belli, Francesca; Condello, Maria; Arancia, Giuseppe; Seiler, Nikolaus

doi:10.3892/ijo.29.4.947

Cited by 19 publications

(36 citation statements)

References 21 publications

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“…Controversially, tumor cells acquire resistance to grow in an oxidative environment, developing also a MDR mechanism to overwhelm chemotherapy. However, in recent years, we observed that cytotoxicity induced by ROS, downstream the spermine metabolites by BSAO, was greater in human tumor MDR LoVo cells than the wild-type counterpart, Agostinelli et al (18,33). In addition, our findings also showed that ROS formed by the combination BSAO/spermine are not only able to prevent tumor cell growth, but also prevents mass tumor growth.…”

Section: Discussionsupporting

confidence: 63%

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

Amendola

Cervelli

Fratini

et al. 2013

International Journal of Oncology

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Abstract.The most frequent interventions in cancer therapy are currently the destruction of cells by irradiation or administration of drugs both able to induce radical formation and toxic metabolites by enzyme-catalyzed reactions. The aim of this study was to determine the cell viability of cells undergoing a DNA damage threshold accomplished by ROS overproduction via both ectopic expression of murine spermine oxidase (mSMOX) and bovine serum amine oxidase (BSAO) enzymes. Low dose of X-irradiation delivers a challenging dose of damage as evaluated in proficient Chinese hamster AA8 cell line and both deficient transcription-coupled nucleotide excision repair (NER) UV61 cells and deficient base excision repair (BER) EM9 cells, at 6 and 24 h after exposure. The priming dose of ROS overexposure by mSMOX provokes an adaptive response in N18TG2, AA8 and EM9 cell lines at 24 h. Interestingly, in the UV61 cells, ROS overexposure by mSMOX delivers an earlier adaptive response to radiation. The enzymatic formation of toxic metabolites has mainly been investigated on wild-type (WT) and multidrug-resistant (MDR) cancer cell lines, using and spermine as substrate of the BSAO enzyme. MDR cells are more sensitive to the toxic polyamine metabolites than WT cells, thus indicating a new therapeutic strategy to overcome MDR tumors. Since SMOX in mammals is differentially activated in a tissue-specific manner and cancer cells can differ in terms of DNA repair and MDR capabilities, it could be of interest to simultaneously treat with very low dose of X-rays and/or to alter SMOX metabolism to generate a differential response in healthy and cancer tissues. IntroductionMammalian cells evolved and constantly live in a highly reactive oxidative environment. In the mammalian organism H 2 O 2 has a central position within the reactive oxygen species (ROS) family. Its formation by several reactions and its controlled inactivation is the basis of redox homeostasis (1,2), since free radicals are highly cytotoxic. Oxidative stress is the result of interactions with macromolecules among highly reactive hydrogen peroxide (H 2 O 2 ) and singlet oxygen ( ). Besides the major interest in identification and advancement of compounds which are either radical scavengers or antioxidants, ROS can alternate between a positive and negative cellular outcomes (3). Insufficient ROS defense mechanisms are mutagenic and promote cell death, apoptosis and autophagy (4). Recently autophagy and apoptosis stimulus by the presence of an H 2 O 2 -induced pathway in human primary and tumor cell lines and in primary cells (5)

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Section: Discussionsupporting

confidence: 63%

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

Amendola

Cervelli

Fratini

et al. 2013

International Journal of Oncology

Self Cite

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“…In previous reports we discussed the effect of cytotoxic metabolites of spermine, hydrogen peroxide and aldehydes, on several cell lines (10,40), including human melanoma (M14) (11) and mouse melanoma tumor cells (B16-F0) (24). The growth Figure 11.…”

Section: Discussionmentioning

confidence: 99%

“…While, the induction of cell death, in colon adenocarcinoma (LoVo) and melanoma (M14) cancer cells, was potentiated by the combined treatments of BSAO/spermine with lysosomotropic compounds (10,11).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the sensitization of tumor cells to anti-cancer drugs by lysosomotropic compounds, and particularly the sensitization of MDR cells, recommends scrutinizing the potential of lysosomotropic drugs in cancer therapy (10,11,28).…”

Section: Introductionmentioning

confidence: 99%

“…The oxidative deamination of spermine by bovine serum amine oxidase (BSAO: EC 1.4.3.6) generates ammonia and the cytotoxic metabolites hydrogen peroxide and aldehydes (8,10,11).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Agostinelli

Condello²,

Molinari³

et al. 2009

Int J Oncol

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Abstract. It has been confirmed that multidrug resistant (MDR) human melanoma cells are more sensitive than their wild-type counterparts to H 2 O 2 and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. The metabolites formed by BSAO and spermine are more toxic than exogenous H 2 O 2 and acrolein, even though their concentration is lower during the initial phase of incubation due to their more gradual release than the exogenous products. Both wild-type and MDR cells, after pre-treatment with MDL 72527, an inactivator of polyamine oxidase and a lysosomotropic compound, show to be sensitized to subsequent exposure to BSAO/spermine. Evidence of ultrastructural aberrations and acridine orange release from lysosomes is presented in this work that is in favor of the permeabilization of the lysosomal membrane as the major cause of sensitization by MDL 72527. Owing to its lysosomotropic effect, pre-treatment with MDL 72527 amplifies the ability of the metabolites formed from spermine by oxidative deamination to induce cell death. Since it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumor cells, it is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting.

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Reactive oxygen species as a double‐edged sword: The role of oxidative enzymes in antitumor therapy

Rosini

Pollegioni

2021

BioFactors

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A number of approaches have been developed over the years to manage cancer, such as chemotherapy using low-molecular-mass molecules and radiotherapy. Here, enzymes can also find useful applications. Among them, oxidases have attracted attention because of their ability to produce reactive oxygen species (ROS, especially hydrogen peroxide) in tumors and potentially modulate the production of this cytotoxic compound when enzymes active on substrates present in low amounts are used, such as the D-amino acid oxidase and Damino acid couple system. These treatments have been also developed for additional cancer treatment approaches, such as phototherapy, nutrient starvation, and metal-induced hydroxyl radical production. In addition, to improve tumor specificity and decrease undesired side effects, oxidases have been targeted by means of nanotechnologies and protein engineering (i.e., by designing chimeric proteins able to accumulate in the tumor). The most recent advances obtained by using six different oxidases (i.e., the FAD-containing enzymes glucose oxidase, D-and L-amino acid oxidases, cholesterol oxidase and xanthine oxidase, and the copper-containing amine oxidase) have been reported. Anticancer therapy based on oxidase-based ROS production has now reached maturity and can be applied in the clinic.

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Sensitization of human colon adenocarcinoma cells (LoVo) to reactive oxygen species by a lysosomotropic compound

Cited by 19 publications

References 21 publications

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Reactive oxygen species as a double‐edged sword: The role of oxidative enzymes in antitumor therapy

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