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Inhibition of Bcl-2

In This Section:

Bcl-2 in Normal Cells

The cells of the immune system must be able to rapidly expand to fight infections and then decrease in number when a threat has been overcome. One way the body controls the number of immune cells is through the carefully-controlled process of apoptosis, or programmed cell death.

A human head and torso are shown on the left with the lymphatic system highlighted. A call-out bubble coming from one of the lymph nodes shows a close-up view of several immune cells. One of the cells has undergone apoptosis, illustrated by the fact that it has broken into several gray globules.

A human head and torso are shown on the left with the lymphatic system highlighted. A call-out bubble coming from one of the lymph nodes shows a close-up view of several immune cells. One of the cells has undergone apoptosis, illustrated by the fact that it has broken into several gray globules.

The Bcl-2 family of proteins is critical for regulation of apoptosis in lymphocytes and many other cells in the body. There are both pro-survival and pro-apoptotic Bcl-2 family members. When activated, some pro-apoptotic family members, such as Bax and Bak, form pores in the outer membrane of the mitochondria, allowing the release of proteins that initiate apoptosis.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' Several red pro-apoptotic proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” Several red pro-apoptotic proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

Pro-survival proteins such as Bcl-2 maintain the integrity of the mitochondria by preventing activation of pro-apoptotic family members.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis.

Other pro-apoptotic Bcl-2 family members called BH3-only proteins promote apoptosis by preventing the inhibitory activity of Bcl-2 and other pro-survival family members. This allows pro-apoptotic family members to form pores in the outer mitochondrial membrane and initiate cell death.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' Small circular red proteins bound to Bcl-2 are labeled, 'Pro-apoptotic (BH3-only).'

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” Small circular red proteins bound to Bcl-2 are labeled, “Pro-apoptotic (BH3-only).” Several red pro-apoptotic Bax/Bak proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

 

Bcl-2 in Cancer Cells

Bcl-2 family members have been widely implicated in cancer. Elevated levels of Bcl-2 have been identified in a number of lymphoma types. Increased expression of the Bcl-2 gene can be caused by chromosomal translocation, gene amplification, DNA hypomethylation, and loss of regulatory microRNA expression. When levels of Bcl-2 are high, pro-apoptotic proteins cannot form pores in the mitochondrial membrane. This allows cells to ignore signals to undergo apoptosis, which may contribute to the formation and growth of tumors.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis. Screen text reads, “Elevated levels of Bcl-2 allow cells to ignore signals to undergo apoptosis.”

For example, high levels of Bcl-2 help cancer cells survive after they have been damaged by chemotherapeutic drugs. This may help explain why elevated expression of Bcl-2 is associated with poor prognosis of non-Hodgkin lymphoma patients.

A layer of pink normal cells is shown in the background and a mass of green tumor cells is in the foreground. Small yellow molecules representing chemotherapeutic drugs are present. The tumor cells are not undergoing apoptosis in response to the chemotherapy.

A layer of pink normal cells is shown in the background and a mass of green tumor cells is in the foreground. Small yellow molecules representing chemotherapeutic drugs are present. The tumor cells are not undergoing apoptosis in response to the chemotherapy.

 

Inhibiting Bcl-2

There are numerous ongoing efforts to interfere with Bcl-2 and its fellow pro-survival family members to help restore the sensitivity of cancer cells to pro-apoptotic signals. Several small molecules—including one called ABT-263—have been designed to mimic BH3-only proteins. These BH3 mimetics bind to Bcl-2 and some other pro-survival family members, allowing Bax and other pro-apoptotic proteins to create pores in the outer mitochondrial membrane and commit the cell to apoptotic death.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' Small circular purple molecules bound to Bcl-2 are labeled, 'Pro-apoptotic ABT-263 (BH3-only mimetic).'

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” Small circular purple molecules bound to Bcl-2 are labeled, “Pro-apoptotic ABT-263 (BH3-only mimetic).” Several red pro-apoptotic Bax/Bak proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

ABT-263 induces death of lymphoma cells grown in cell culture and can also inhibit tumor growth in mouse models of lymphoma.

There have also been a number of promising results from preclinical studies of ABT-263 in combination with other therapies, including standard chemotherapeutic regimens, Rituxan® (rituximab), and the mTOR inhibitor rapamycin. ABT-263 and other Bcl-2 inhibitors are being tested in clinical trials for lymphomas and other types of cancer.

A group of green figures represent clinical trials participants. Three gray boxes on the left of the screen are labeled, 'Phase 0,' 'Phase I,' and 'Phase II' and are connected by arrows. Screen text reads, 'Bcl-2 inhibitors are being tested in clinical trials for lymphomas and other types of cancer.'

A group of green figures represent clinical trials participants. Three gray boxes on the left of the screen are labeled, “Phase 0,” “Phase I,” and “Phase II” and are connected by arrows. Screen text reads, “Bcl-2 inhibitors are being tested in clinical trials for lymphomas and other types of cancer.”

More Information

This table lists several drugs that target Bcl-2 family members.

 Research NameGeneric NameTrade NameDrug Type
Bcl-2 targeted drugs--Oblimersen sodiumGenasense®Antisense oligonucleotide
 AT-101Gossypol (levo gossypol)--Small molecule
 GX15-070Obatoclax--Small molecule
 ABT-263----Small molecule

None of the agents listed on this table have been approved by the FDA for treatment of lymphoma; however, all of these drugs are being tested in clinical trials for lymphoma and/or other types of cancer. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

Specificity of Bcl-2 inhibitors: Most small molecule Bcl-2 inhibitors also bind to and inhibit other pro-survival Bcl-2 family members, including Bcl-XL, Bcl-w, and Mcl-1. ABT-263 binds with high affinity to Bcl-2, Bcl-XL, and Bcl-w, but interacts weakly with Mcl-1.

 

Antisense oligonucleotides anti-Bcl-2 drugs: Genasense® is an antisense oligonucleotide (short piece of single-stranded DNA) that targets Bcl-2 messenger RNA. When Genasense® is present, the Bcl-2 messenger RNA cannot be translated into Bcl-2 protein and is instead degraded. The result is lower levels of Bcl-2 protein in the cell, which makes the cell more susceptible to apoptosis.

Self Test

Questions

  1. BH3 mimetics directly induce apoptosis.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      BH3 mimetics interfere with the activity of pro-survival proteins, which allows pro-apoptotic proteins to initiate cell death.
    2. False - Correct.
      BH3 mimetics interfere with the activity of pro-survival proteins, which allows pro-apoptotic proteins to initiate cell death.