The proteasome: a novel target for anticancer therapy

ABSTRACT

The proteasome is an ubiquituous enzyme complexthat plays a critical role in the degradation of manyproteins involved in cell cycle regulation, apoptosisand angiogenesis. Since these pathways are fundamentalfor cell survival and proliferation, particularlyin cancer cells, the inhibition of proteasome is anattractive potential anticancer therapy. Bortezomib(Velcade, formerly PS-341) is an extremely potentand selective proteasome inhibitor that shows strongactivity in in vitro and in vivo laboratory studiesagainst many solid and hematologic tumor types.Moreover, bortezomib, mainly by inhibition of theNF-êB pathway, has a chemosensitizing effect whenadministered together with other antitumoral drugs.Clinical phase I trials, showed good tolerance ofbortezomib at doses that achieved a desired degreeof proteasome inhibition. Phase II studies showedhigh response rates in refractory multiple myelomapatients, which led to the accelerated approval ofbortezomib by the Food and Drug Administration(FDA) and the European Medicines Agency (EMEA)for this indication. A phase III trial comparing bortezomibto dexamethasone in refractory/relapsed multiplemyeloma patients had to be halted due to a survivaladvantage in the bortezomib arm. Additionalstudies are focusing in the potential benefit of bortezomibin newly diagnosed multiple myeloma patients.In other solid and hematological malignancies,phase II studies with bortezomib alone or incombination are ongoing with encouraging results,particularly in lung cancer and lymphoma

RESUMEN

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