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Targeted Therapies for Multiple Myeloma Tutorial

Inhibition of the NF-kB Pathway

In This Section:

NF-kB in Normal Cells

The balance between the synthesis and degradation of key regulatory proteins determines the activities of several cellular signaling pathways. The ubiquitin-proteasome system is one mechanism cells use to degrade damaged or unneeded proteins. This system targets proteins involved in such key cellular processes as cell proliferation, growth, and survival.

The cytoplasm and nucleus of a cell are shown. A large cylindrical-shaped protein complex in the cytoplasm is labeled 'proteasome.' A small protein labeled 'protein' linked to small red circles labeled 'ubiquitin' is shown near the proteasome. The screen text reads, 'The ubiquitin-proteasome system is one mechanism cells use to degrade damaged or unneeded proteins.'

One example of a protein that is regulated by the ubiquitin-proteasome system is NF-kB. NF-kB is normally sequestered in the cell's cytoplasm by a protein called Inhibitor of NF-kB, or IkB. In this state, the NF-kB pathway is inactive.

The cytoplasm and nucleus of a cell are shown. A proteasome is present in the cytoplasm. Two proteins labeled 'IkB' and 'NF-kB' are in a complex in the cytoplasm. The IkB-NFkB complex is gray, indicating that it is inactive.

A number of signaling pathways activate NF-kB. They do so by phosphorylating IkB, which makes it a target for ubiquitinylation. The added ubiquitin molecules mark IkB for degradation by proteasomes.

The nucleus and cytoplasm of a cell are shown. A proteasome is shown in the cytoplasm. Small globular structures representing proteins in two signaling pathways are shown glowing, indicating that the signaling pathways are active. The pathways end near the IkB-NFkB complex.

The nucleus and cytoplasm of a cell are shown. A proteasome is shown in the cytoplasm. The IkB-NFkB complex has moved toward the proteasome. Small red circles representing ubiquitin have been added to IkB. NFkB is gray, indicating that it is inactive.

Once IkB has been degraded, NF-kB is free to move to the cell's nucleus, where it helps induce expression of a number of genes that promote cell survival and proliferation.

The nucleus and cytoplasm of a cell are shown. A proteasome is shown in the cytoplasm. IkB is now represented by a long yellow strand, indicating that the protein has been unfolded. The unfolded IkB is entering the proteasome. NFkB is now separate from IkB and is colored, indicating that it is active. NFkB is moving toward the nucleus of the cell.

NF-kB in Cancer Cells

The NF-kB signaling pathway is highly active in multiple myeloma as well as in many other cancers.

The nucleus and cytoplasm of a cell are shown. Two proteasomes are shown in the cytoplasm. One active NfKB protein is shown moving away from an IkB protein that is being degraded by a proteasome. An activated signaling pathway is shown phosphorylating another IkB protein that is in complex with NFkB. The screen text reads, 'The NF-kB pathway is highly active in most myelomas.'

Inhibition of this pathway has been shown to undermine the survival of myeloma cells, making NF-kB an attractive therapeutic target.

Inhibiting NF-kB

Interfering with the activity of the ubiquitin-proteasome system is one strategy for inhibiting NF-kB activity in cancer cells. For reasons not fully understood, cancer cells seem to be more sensitive to proteasome inhibition than normal cells.

Velcade® (bortezomib) is an example of a proteasome inhibitor. Velcade® binds strongly to the proteasome, preventing it from degrading IkB and other target proteins. This allows IkB to accumulate in the cytoplasm and keep NF-kB in its inactive state.

The cytoplasm of a cell is shown. A proteasome is present. An IkB-NFkB complex is near the proteasome; however, IkB is not being degraded by the proteasome because the proteasome is bound by a small purple ball representing the drug Velcade. The screen text reads, 'Velcade prevents the proteasome from degrading IkB and other target proteins.'

The reduction in NF-kB activity and the modification of other signaling pathways upon proteasome inhibition collectively reduce cell proliferation and increase the apoptosis of multiple myeloma cells.

A mass of green tumor cells is shown in the middle of a sheet of pink normal cells. Several of the cancer cells have fragmented into small gray vesicles, indicating that they have undergone apoptosis. The screen text reads, 'Proteasome inhibition reduces NF-kB activity and increases apoptosis.'

Velcade® has been approved by the FDA for the treatment of multiple myeloma based on evidence from clinical trials that the drug can delay disease progression and increase overall survival in myeloma patients.

Velcade® continues to be studied in clinical trials for multiple myeloma and other cancers as both a single agent and in combination with standard therapies, including immune system modulators such as Thalidomid® and Synovir®, and other targeted therapies.

More Information

Proteasome Inhibitors

This table lists several proteasome inhibitors that are being tested in clinical trials for multiple myeloma. Agents that have been approved by the FDA for treatment of multiple myeloma are marked with an asterisk. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

 Research NameGeneric NameTrade Name(s)Drug Type
Proteasome InhibitorsPS-341BortezomibVelcade®*Small molecule
 PR-171Carfilzomib--Small molecule


Self Test

Questions

  1. Velcade® directly inhibits NF-kB.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      Velcade® inhibits NF-kB indirectly by interfering with the activity of the cell's proteasome. Inhibition of the proteasome will alter the activity of several signaling pathways, not only the NF-kB signaling pathway.
    2. False - Correct.
      Velcade® inhibits NF-kB indirectly by interfering with the activity of the cell's proteasome. Inhibition of the proteasome will alter the activity of several signaling pathways, not only the NF-kB signaling pathway.