The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma.
Single-agent bortezomib, a potent, selective, and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the MCL patients; however, complete remission rates are low and duration of response proved to be relatively short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Rational combination treatment and schedules require profound knowledge of underlying molecular mechanisms. Here we show that single-agent bortezomib treatment of MCL cell lines leads to G2/M arrest and induction of apoptosis accompanied by downregulation of EIF4E and CCND1 mRNA but upregulation of p15(INK4B) and p21 mRNA. We further present synergistic efficacy of bortezomib combined with cytarabine in MCL cell lines. Interestingly this sequence-dependent synergistic effect was seen almost exclusively in combination with AraC, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.
Helmholtz Centre Munich, Muenchen, Germany. hutter@helmholtz-muenchen.de
Grit
G
Hutter
Malte
M
Rieken
Alessandro
A
Pastore
Oliver
O
Weigert
Yvonne
Y
Zimmermann
Marc
M
Weinkauf
Wolfgang
W
Hiddemann
Martin
M
Dreyling
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004334:Drug Administration Schedule; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib