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¹ Dipartimento di Neuroscienze e Tecnologie Biomediche and ² Consorzio MIA, Università di Milano-Bicocca, Monza, Milano, Italy

Requests for reprints: Giovanni Tredici, Dipartimento di Neuroscienze e Tecnologie Biomediche, Facoltà di Medicina e Chirurgia, Via Cadore 48, 20052 Monza, Milan, Italy. Phone: 39-02-64488115; Fax: 39-02-64488250. E-mail: giovanni.tredici{at}unimib.it

Combined anticancer therapy using platinum compounds and antitubulins has increased the risk of neurotoxicity. However, the combination of low-dose cisplatin (CDDP) with toxic doses of paclitaxel significantly reduces cellular death in a human neuroblastoma SH-SY5Y cell line. To analyze the mechanisms of this protection, we evaluated various signaling molecules possibly involved in apoptosis and some relevant cell cycle regulatory proteins. CDDP does not interfere with the tubulin-stabilizing action of paclitaxel. The evaluation of molecular pathways involved in apoptosis indicates that the Bcl-2 but not the caspases may be involved in the CDDP protection of paclitaxel-induced apoptosis. The increase in p53 protein and its nuclear accumulation suggests a possible involvement of p53 in CDDP protection. The use of the chemical inhibitor of p53, pifithrin , excluded this possibility. The study of cyclins and the flow cytometric analysis (fluorescence-activated cell sorting) suggest that CDDP exerts a protective action by blocking cells early in the cell cycle. The determination of the mitotic index indicates that CDDP prevents cells from reaching the mitosis. We concluded that low doses of CDDP are protective against toxic doses of paclitaxel and that the possible mechanism of this protection is that the CDDP prevents human neuroblastoma SH-SY5Y cells from achieving mitosis.

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Received 2/22/05; revised 7/ 7/05; accepted 7/15/05.