Bcl-2
Bcl-2 is the prototype for a family of genes that can be either pro-apoptopic ? Bax, Bak and Bok among others ? or anti-apoptopic ? including Bcl-2, Bcl-xL, Bcl-w also among an assortment of others.
There are a number of theories concerning how the Bcl2 gene family exert their pro- or anti- apoptopic effect. An important one states that this is achieved by activation or inactivation of an inner mitochondrial permeability transition (PT) pore which is involved in the regulation of matrix Ca2+, pH and voltage. It is also thought that some Bcl-2 family proteins can induce (pro-apoptopic members) or inhibit (anti-apoptopic memberts) the release of cytochrome c in to the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Zamzami et al. (1998) suggest that the release of cytochrome c is in fact mediated by effects on the PT pore of the inner mitochondrial membrane, linking the theories.
Cancer and targeted therapies
The Bcl-2 gene has been implicated in a wide variety of cancers, including melanoma, breast, prostrate and lung carcinomas. It is also thought to be involved in resistance to conventional cancer treatment (Bast et al., 2000).
In B-cell lymphoma, a chromosome translocation occurs ? t(14; 18) ? which places the Bcl-2 gene next to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of anti-apoptopic Bcl-2 protein (Hockenbery et al., 1990). This decreases the propensity of these cells for undergoing apoptosis.
An antisense oliogonucleotide drug Genasense (G3139) has been developed to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed. It was shown that the proliferation of human leukemia cells (with t(14;18) lymphoma) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA (Dias and Stein, 2002).
These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway (Mavoromatis and Cheson, 2004). A problem so far identified is that SCLC cells overexpress not only Bcl-2 but also Bcl-xL, which also acts anti-apoptopicly. Also tumour cells have the ability to switch expression from Bcl-2 to Bcl-xL. A group has developed a 'bispecific' antisense oligonucleotide which can simultaneously target both mRNA strands. This has been proven preclinically to be a potent tumour inhibitor (Gautschi et al., 2002).
References
- Dias N and Stein CA. (2002). Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. European Journal of Pharmaceutics and Biopharmaceutics, 54:263-269
- Gautschi O, Zangemeister-Wittke U, Stahel RA. (2002). Comment on "A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer", by C. M. Rudin et al. Ann Oncol, 13:539-545.
- Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. (1990). Bcl-2 is an inner mitochondiral membrane protein that blocks programmed cell death. Nature, 348:334-336
- Mavromatis BH and Cheson BD. (2004). Novel therapies for chronic lymphocytic leukemia. Blood Reviews, 18:137-148
- Zamzami Z, Brenner C, Marzo I, Susin SA, Kroemer G. (1998). Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. 16:2265-2282
