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Direct oxidative DNA damage, apoptosis and radio sensitivity by spermine oxidase activities in mouse neuroblastoma
R Amendola1, A Bellini, M Cervelli
1Istituto per la Radioprotezione, ENEA, CR Casaccia, Via Anguillarese 301, 00060 Rome, Italy. amendola@casaccia.enea.it
Abstract:
In mammals, the polyamines affect cell growth, differentiation, and apoptosis; their levels are increased in malignant and proliferating cells, thus justifying an interest in a chemotherapeutic approach to cancer. The flavoprotein SMO is the most recently characterized catabolic enzyme, preferentially oxidizing SPM to SPD, 3-aminopropanal and H(2)O(2). In this report, we describe a novel functional characterization of the recently cloned splice variant isoforms from mouse brain, encoding, among others, the nuclear co-localized spermine oxidase mSMOmu. The over-expression of the active isoforms mSMOalpha and mSMOmu, and the inactive mSMOdelta and mSMOgamma in mouse neuroblastoma cells, demonstrated the first evidence of the direct oxidative DNA damage by the SMO activities, either alone or, in a higher extent, when associated with radiation exposure, thus working as radio sensitizer. These effects were reverted by treatment with 50 muM and 100 muM doses of the inhibitor of SMO activity MDL 72,527. The over-expression of all SMO isoforms failed to influence the expression of the regulating enzymes of polyamines metabolism ODC and SSAT. Dealing with the unbalanced tissue specific SMO activities, these results could indicate a new direction to tailor chemotherapy-associated radiotherapy, improving dose-rate protocol and allowing the modulation of deleterious side effects on healthy tissues.
Insights
Spermine oxidase (SMO) enzymes directly damage DNA, enhancing radiation therapy effectiveness in cancer cells. Inhibiting SMO activity with MDL 72,527 reversed these effects, suggesting new therapeutic strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Polyamines are crucial for cell growth, differentiation, and apoptosis, with elevated levels in malignant cells.
- Spermine oxidase (SMO) is a flavoprotein enzyme that catabolizes spermine (SPM) to spermidine (SPD), producing hydrogen peroxide.
- Cancer cells exhibit increased polyamine levels, making them targets for chemotherapeutic intervention.
Purpose of the Study:
- To functionally characterize novel splice variant isoforms of mouse spermine oxidase (SMO) from mouse brain.
- To investigate the role of SMO activity in direct oxidative DNA damage and its potential as a radiosensitizer in cancer therapy.
- To explore the therapeutic potential of SMO inhibition in cancer treatment.
Main Methods:
- Cloning and over-expression of different SMO splice variant isoforms (mSMOalpha, mSMOmu, mSMOdelta, mSMOgamma) in mouse neuroblastoma cells.
- Assessing direct oxidative DNA damage induced by SMO activity, alone and in combination with radiation exposure.
- Evaluating the effect of the SMO inhibitor MDL 72,527 on SMO-induced DNA damage and radiosensitization.
- Analyzing the impact of SMO isoform over-expression on the expression of polyamine metabolism enzymes ODC and SSAT.
Main Results:
- Over-expression of active SMO isoforms (mSMOalpha, mSMOmu) induced direct oxidative DNA damage.
- SMO activity acted as a radiosensitizer, significantly increasing DNA damage when combined with radiation.
- The SMO inhibitor MDL 72,527 effectively reversed the observed DNA damage and radiosensitizing effects.
- Over-expression of SMO isoforms did not alter the expression of ODC and SSAT, key regulators of polyamine metabolism.
Conclusions:
- SMO enzymes directly contribute to oxidative DNA damage and can enhance the efficacy of radiotherapy.
- Targeting SMO activity with inhibitors like MDL 72,527 offers a potential strategy for improving cancer chemotherapy and radiotherapy.
- Understanding tissue-specific SMO activity may lead to tailored treatment protocols to modulate side effects on healthy tissues.
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