Antiapoptotic effects of roscovitine on camptothecin-induced DNA damage in neuroblastoma cells |
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Authors: | Javier G Pizarro Jaume Folch Felix Junyent Ester Verdaguer Carme Auladell Carlos Beas-Zarate Mercè Pallàs Antoni Camins |
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Institution: | 1.Centros de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Unitat de Farmacologia i Farmacognòsia. Facultat de Farmàcia, Institut de Biomedicina (IBUB),Universitat de Barcelona, Nucli Universitari de Pedralbes,Barcelona,Spain;2.Unitat de Bioquímica, Facultat de Medicina i Ciències de la Salut, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED),Universitat Rovira i Virgili,Reus (Tarragona),Spain;3.Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara and División de Neurociencias, Centro de Investigación Biomédica de Occidente, (CIBO),Instituto Mexicano del Seguro Social (IMSS),Guadalajara,Mexico;4.Departament de Biologia Cellular, Facultat de Biologia,Universitat de Barcelona,Barcelona,Spain |
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Abstract: | In the present study dopaminergic neuroblastoma B65 cells were exposed to Camptothecin (CPT) (0.5–10 μM), either alone or
in the presence of roscovitine (ROSC). The results show that CPT induces apoptosis through the activation of ataxia telangiectasia
mutated (ATM)-induced cell-cycle alteration in neuroblastoma B65 cells. The apoptotic process is mediated through the activation
of cystein proteases, namely calpain/caspases. However, whereas a pan-caspase inhibitor, zVADfmk, inhibited CPT-mediated apoptosis,
a calpain inhibitor, calpeptin, did not prevent cell death. Interestingly, CPT also induces CDK5 activation and ROSC (25 μM)
blocked CDK5, ATM activation and apoptosis (as measured by caspase-3 activation). By contrast, selective inhibition of ATM,
by KU55933, and non-selective inhibition, by caffeine, did not prevent CPT-mediated apoptosis. Thus, we conclude that CDK5
is activated in response to DNA damage and that CDK5 inhibition prevents ATM and p53ser15 activation. However, pharmacological
inhibition of ATM using KU55933 and caffeine suggests that ATM inhibition by ROSC is not the only mechanism that might explain
the anti-apoptotic effects of this drug in this apoptosis model. Our findings have a potential clinical implication, suggesting
that combinatory drugs in the treatment of cancer activation should be administered with caution. |
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