Pancreatic CancerHillol Sarkar | March 8, 2015

Hillol.Sarkar@ago-inc.com | http://goo.gl/0qEiJD | Advanced Generation Algorithm

Proteasome 26S inhibition induces apoptosis and limits growth of pancreatic cancer

Keywords: cell cycle; p21; mouse xenografts; PS-341; NF-κB; 26S; CDK; CPT11 + PS-341

AbstractThe 26S Proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS-341, a Dipeptide Boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. http://goo.gl/kw8nMP

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)

Defects in NF-κB results in increased susceptibility to apoptosis leading to increased cell death. This is because NF-κB regulates anti-apoptotic genes especially theTRAF1 and TRAF2 and, therefore, checks the activities of the caspase family of enzymes, which are central to most apoptotic processes.[53]

In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.

http://en.wikipedia.org/wiki/NF-%CE%BAB

NF-κB was discovered by Dr. Ranjan Sen in the lab of Nobel Prize laureate David Baltimore via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells.

http://en.wikipedia.org/wiki/David_Baltimore

Proteasome

The main function of the proteasome is to degrade damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

CPT-11/PS-341 therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF-κB activation indicating this therapy was effective at the cancer cell level.

http://en.wikipedia.org/wiki/Proteasome