title: An analysis of the safety profile of proteasome inhibitors for treating various cancers.
abstract: BACKGROUND
  Emerging evidence demonstrates that the ubiquitin-proteasome pathway is a promising target for cancer therapy. Bortezomib (Velcade) exhibits great efficacy against multiple myeloma (MM) since the first clinical application. However, there are still several limitations associated with the use of bortezomib, including severe toxicities. To overcome bortezomib's shortcomings and to improve its safety profile, several second-generation proteasome inhibitors, for example, carfilzomib, ixazomib, oprozomib and marizomib, have been developed and currently tested in various clinical trials.
  
  
  METHODS
  A literature search was carried out using PubMed and Google Scholar. The activity and safety profiling of proteasome inhibitors in treatment of various cancers were reviewed.
  
  
  CONCLUSIONS
  Bortezomib, as a single or in combination therapy, demonstrates efficacy against MM or other hematological malignancies in clinical settings. However, it encounters two major problems, the acquired resistance and the severe side effects. Future direction in bortezomib-based therapy should focus on how to increase or retain its efficacy but improve its safety profile through, for example, rational combination therapies. Second-generation proteasome inhibitors have shown benefits in both overcoming bortezomib resistance and reducing related side effects, although these encouraging results should be further confirmed in a larger clinic population.
authors.affiliation: Harbin Institute of Technology, School of Life Science and Technology , 303 Building 2E, 2 Yikuang Street, Harbin, Heilongjiang Province, 150001 , PR China +86 0451 86403616 ; yanghj@hit.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Fangxia
authors.initials: F
authors.lastname: Guan
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Qing Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Huanjie
authors.initials: H
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib
keywords: anticancer therapy; clinical trials; proteasome inhibitors; safety profile