Proteasome inhibitors in cancer therapy.
The ubiquitin-proteasome pathway is involved in intracellular protein turnover and plays an essential function in many cellular processes, thus contributing to cellular homeostasis. The observation that proteasome inhibitors are able to induce apoptosis preferentially in tumor cells opened the way to their use as potential drugs. One of these drugs, bortezomib, was introduced in cancer therapy and its use was approved for the treatment of multiple myeloma and mantle cell lymphoma. The investigation of the mechanisms through which bortezomib causes cell death of cancer cells showed that this drug affects many cellular pathways and many of its effects cannot be related to proteasome inhibition. These observations, as well as the occurrence of bortezomib resistance observed in some myeloma patients treated with this drug, prompted the study of new proteasome inhibitors. These studies have lead to a new generation of proteasome inhibitors, some of them exhibiting the property of selective proteasome inhibition and efficacy in cancer therapy without inducing the side effects elicited by bortezomib. The ensemble of these drugs offers the scenario of the possible development of a family of proteasome inhibitors, contributing a drug arsenal for the therapy of cancer and other diseases.
Testa
Ugo
U
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. ugo.testa@iss.it
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib