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Rationale for new RAR-based treatment for Mantle Cell Lymphoma (MCL)

MCL is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavourable prognosis. RA isomers significantly inhibit the proliferation of both primary MCL cultures and established cell lines.

RA induces cell accumulation in G0/G1 together with a marked up-regulation of p27Kip-1 by inhibiting ubiquitination and proteasome-dependent degradation of the protein. Most of RA-induced p27Kip-1 binds to cyclin D1/CDK4 complexes, thus contributing to the inhibit Cdk4 kinase activity and pRb hypophosphorylation.

Experiments with receptor-selective ligands indicate that RARa co-operates with RXRs in mediating RA-dependent MCL cell growth inhibition. MCL is characterized by a constitutively active PI3-K signalling whose pharmacologic inhibition severely impairs the proliferation of these cells.

Interestingly, RA treatment decreases the levels of phosphorylated, active Akt in these cells, suggesting the possibility that the antiproliferative effects exerted by RA in MCLs are at least in part mediated by RA-induced inhibition of the PI3-K/Akt signalling.

IFN-a enhances the antiproliferative activity exerted by RA in MCL cells and, more importantly, the 9-cis-RA/IFN-a combination also induces caspase-dependent apoptosis.

These findings provide the rationale for the evaluation of the possible efficacy of 9-cis-RA in the treatment of MCL patients. The drawing up of a specific clinical trial is in progress.

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Cancer Bio-Immunotherapy Unit
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