DIRECT OXIDATIVE DNA DAMAGE, APOPTOSIS AND RADIO SENSITIVITY BY SPERMINE OXIDASE ACTIVITIES IN MOUSE NEUROBLASTOMA CELLS

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 H2O2. 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 mSMOA. The over-expression of the active isoforms mSMOa and mSMOA, and the inactive mSMOy and mSMOg 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 AM and 100 AM 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.