Combination of proteasomal inhibitors lactacystin and MG132 induced synergistic apoptosis in prostate cancer cells.
The proteasome inhibitor Velcade (bortezomib/PS-341) has been shown to block the targeted proteolytic degradation of short-lived proteins that are involved in cell maintenance, growth, division, and death, advocating the use of proteasomal inhibitors as therapeutic agents. Although many studies focused on the use of one proteasomal inhibitor for therapy, we hypothesized that the combination of proteasome inhibitors Lactacystin (AG Scientific, Inc., San Diego CA) and MG132 (Biomol International, Plymouth Meeting, PA) may be more effective in inducing apoptosis. Additionally, this regimen would enable the use of sublethal doses of individual drugs, thus reducing adverse effects. Results indicate a significant increase in apoptosis when LNCaP prostate cancer cells were treated with increasing levels of Lactacystin, MG132, or a combination of sublethal doses of these two inhibitors. Furthermore, induction in apoptosis coincided with a significant loss of IKKalpha, IKKbeta, and IKKgamma proteins and NFkappaB activity. In addition to describing effective therapeutic agents, we provide a model system to facilitate the investigation of the mechanism of action of these drugs and their effects on the IKK-NFkappaB axis.
Shirley
Robert B
RB
Department of Urology, Medical College of Georgia, Augusta, GA 30912, USA.
Kaddour-Djebbar
Ismail
I
Patel
Dimpu M
DM
Lakshmikanthan
Vijayabaskar
V
Lewis
Ronald W
RW
Kumar
M Vijay
MV
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D061988:Proteasome Inhibitors; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; C491731:IKBKG protein, human; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; C067713:lactacystin; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine