Antineoplastic therapy in colorectal cancer through proteasome inhibition.
Upregulation of nuclear factor (NF)-kappaB is found in many forms of cancer. Activation of NF-kappaB in cancer cells by chemotherapy or radiation can blunt the ability of this therapy to induce cell death. Proteasome inhibitors stimulate apoptosis in part via prevention of NF-kappaB activation. We sought to determine whether constitutive NF-kappaB activity is present in human colon cancer. In addition we studied whether alterations of NF-kappaB activity with a proteasome inhibitor would prevent colon cancer cell growth and induce apoptosis. We demonstrated constitutive transcriptional activation of NF-kappaB in SW48 and SW116 colon cancer cells by luciferase and electromobility shift assays. This was confirmed by p65 immunostaining. This activity was further induced in the presence of chemotherapy. In colon cancer specimens constitutive activation of NF-kappaB was observed in the majority of tumors. Treatment with the proteasome inhibitor (MG-132) inhibited growth and also stimulated apoptosis of colon cancer cells. We conclude that inhibition of NF-kappaB activation may be a logical therapy for certain cancers. This can be done via specific approaches on molecules necessary for keeping NF-kappaB inactivated in the cytoplasm. Other potentially useful ways to promote apoptosis in cancer cells include the utilization of proteasome inhibitors. Such inhibitors are currently being evaluated in clinical trials.
Hochwald
Steven N
SN
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Lind
D Scott
DS
Malaty
John
J
Copeland
Edward M
EM
Moldawer
Lyle L
LL
MacKay
Sally L D
SL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003546:Cysteine Endopeptidases; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004792:Enzyme Precursors / Q000032:analysis; D018014:Gene Transfer Techniques; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D003841:Deoxycytidine; D008156:Luciferases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000093542:Gemcitabine