Bcl-2
Therapeutic interests
and roles within disease
The Importance of Apoptosis
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Apoptosis is fundamental in a plethora of processes. Cell population must be kept fairly constant through a stable equilibrium between cell proliferation and cell apoptosis. Roles of apoptosis include (but aren’t limited to):
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Eliminating superfluous cells during development in order to shape the embryo
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Eliminating neurons to match the number of target cells during development
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Limiting pathogen spread by eliminating infected cells
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Eliminating self-recognising immune cells to prevent autoimmunity
The cell is committed to apoptosis when the outer mitochondrial membrane becomes more permeable, allowing cytochrome c and other apoptotic factors into the cytosol. This activates the caspase cascade, the ‘point of no return’. The nuclei and cytoplasm then condense. The cell’s contents become encased in ‘apoptotic bodies’ which are engulfed by phagocytes due to a signal on their surface. Finally, these are digested by fusion with lysosomes.
Bcl-2 has an anti-apoptotic role and so is crucial in cell survival. By inhibiting Bak and Bax which together form a permeability transition pore in the outer mitochondrial membrane, it prevents the intrinsic pathway of apoptosis. Therefore, it follows that defects in Bcl-2 can cause serious pathology.
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References:
[1] Czabotar P. E., Lessene G., Strasser A. & Adams J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nature reviews. Molecular cell biology 15, 49–63, doi: (2014).10.1038/nrm3722 [Nature]
Bcl-2 in Pathology and as a Drug Target
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Defects in Bcl-2 are mainly associated with cancers and autoimmunity. A result of preventing apoptosis is that a larger number of cells live long enough to acquire oncogenic mutations. Overexpression of anti-apoptotic Bcl-2 leads to a low incidence of lymphoma in transgenic mice and it accelerates tumorigenesis driven by other factors such as dysregulated expression of MYC and certain other oncogenes. In 90% of human cases of follicular centre B cell lymphomas, BCL-2 is overexpressed due to a t(14;18) chromosomal translocation. Autoimmunity can also occur due to this anti-apoptotic factor allowing autoreactive B and T cells to survive. Overexpression of BCL-2 or loss of BAK and BAX in mice provoked a fatal immune kidney disease not unlike human systemic lupus erythematosus.
The therapeutic efficacy of most conventional cytotoxic drugs relies on the BCL-2 regulated apoptotic pathway. However, BCL-2 is a very difficult target and most agents that bind it only have moderate affinity and kill cells mainly by off-target effects that do not require BAX or BAK. Based upon the structural knowledge of Bcl-2 and its anti-apoptotic roles that are exploited in cancer it has been possible to formulate therapeutic agents in the shape of BH3 mimetics that induce apoptosis by mimicking the function of the BH3 domain which binds the hydrophobic groove of BCL-2. An example includes ‘navitoclax’ which is taken orally and binds BCL-2 strongly. This drug requires affinity for BCL-2 comparable to those of its natural ligands (eg. BIM) so that it has the ability to displace these ligands and prompt apoptosis. Early clinical trials have assured efficient treatment against blood cell cancers or small cell lung cancer, particularly in patients with chronic lymphocytic leukaemia. In combined treatment, navitoclax can increase efficacy as many conventional agents are likely to work alongside it by decreasing MCL1 levels. This can be used to target tumour cells.
Due to its inhibition of BCL-XL, navitoclax causes a transient acute drop in the number of platelets. A BH3 mimetic that’s only target is BCL-2 will prevent this issue - ABT-199 is a recently developed drug that seems as potent as navitoclax but without affecting platelet population.
Another example is Venetoclax in which acts to abrogate the ability of cancer cells to avoid apoptosis through binding to Bcl-2 acting as a BH3 mimetic of the amphipathic alpha-helix that inserts into the hydrophobic groove of Bcl-2, causing its neutralisation of Bcl-2 inhibition over Bax and Bax homodimer formation and subsequent homo-oligomerisation in the formation of the permeability transition pore, the essential step in induction of apoptosis. It has proven effective in treatment of chronic lymphocytic leukemia.
Bcl-2 as a Drug Target In Industry
Apoptosis and BCL-2
References:
[1] Czabotar P. E., Lessene G., Strasser A. & Adams J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nature reviews. Molecular cell biology 15, 49–63, doi: (2014).10.1038/nrm3722 [Nature]
[2] Hata AN, Engelman JA, Faber AC. The BCL-2 family: key mediators of the apoptotic response to targeted anti-cancer therapeutics. Cancer discovery. 2015;5(5):475-487. doi:10.1158/2159-8290.CD-15-0011. [Pubmed]
[3] Green DR.. A BH3 mimetic for killing cancer cells. Cell (2016) 165(7):1560.10.1016/j.cell.2016.05.080 [PubMed]
This animation created by the biotech company Genentech gives an illustrative overview of how Bcl-2 can be used as a target in cancer treatment by describing the role of Bcl-2 in the apoptosis pathway. The drugs described in the video are BH3 mimetics, as mentioned in the text above. The original video can be found here.