Proteasome inhibition in small-cell lung cancer: preclinical rationale and clinical applications.
Small-cell lung cancer (SCLC) is a tobacco-related malignancy that usually presents in an extensive and therefore incurable stage. Although initially sensitive to platinum agent-based therapy, SCLC rapidly becomes refractory to chemotherapy, leading to disease recurrence and ultimately patient death. Treatment options following failure of first-line platinum agent-based therapy are limited. Small-cell lung cancer is characterized by molecular aberrancies such as overexpression of the antiapoptotic protein Bcl-2, which is regulated in part by the inhibitory IkappaB, a target of the ubiquitin-proteasome degradative pathway. Bortezomib is a proteasome inhibitor that can decrease Bcl-2 expression through diminished IkappaB degradation. Efforts to promote apoptosis in SCLC through the integration of bortezomib into therapy are under way.
Lara
Primo N
PN
University of California Davis Cancer Center, Sacramento, 95817, USA. primo.lara@ucdmc.ucdavis.edu
Bold
Richard J
RJ
Mack
Philip C
PC
Davies
Angela M
AM
Gumerlock
Paul H
PH
Gandara
David R
DR
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000503:physiopathology*; D002986:Clinical Trials as Topic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000503:physiopathology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011719:Pyrazines / Q000494:pharmacology*; D025801:Ubiquitin / Q000502:physiology
D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex