Assessment of apoptosis-inducing effects of docetaxel combined with the proteasome inhibitor PS-341 in human lung cancer cells.
The proteasome inhibitor PS-341 (Bortezomib, Velcade) is currently being combined with taxanes in several clinical trials for treatment of patients with various solid tumors including lung cancers. It has been shown that the combination of Docetaxel (DTX) and PS-341 generates either enhanced or antagonized antitumor effects in different types of cancer in preclinical settings. However, the preclinical evaluation of the DTX and PS-341 combination in human lung cancer cells has not been reported. In this study, the effects of DTX combined with PS-341 on cell survival and apoptosis induction in a panel of human non-small cell lung cancer (NSCLC) cell lines were assessed. We found that PS-341 when combined with DTX led to either enhanced or antagonistic effects on the decrease of cell survival and the induction of apoptosis depending on cell lines and treatment schedules. In general, a treatment schedule administering DTX first followed by PS-341 works better than other schedules in decreasing cell survival and inducing apoptosis. In addition, we examined several molecules regulated by DTX, PS-341, or both agents in order to reveal the underlying mechanisms of synergy and antagonism. Our results suggest that Bcl-2 and survivin are two important proteins that may determine cells' response to DTX/PS-341-induced apoptosis.
Jung
Cecilia S
CS
Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Zhou
Zhongmei
Z
Khuri
Fadlo R
FR
Sun
Shi-Yong
SY
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077143:Docetaxel; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D000077022:Survivin; D043823:Taxoids / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C107489:BIRC5 protein, human; D001897:Boronic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000077022:Survivin; D043823:Taxoids; D000077143:Docetaxel; D000069286:Bortezomib