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Apoptosis: New Approaches To Cancer Therapy
The demise of cells by programmed cell death referred to as apoptosis, a Greek word that means “dropping off“ or “falling off“ as in leaves from a tree, has been recently a topic of intense interest in biomedical sciences. Apoptosis is a well-defined sequence of morphological changes of cells that shrink and condense and then fragment, releasing small membrane-bound apoptotic bodies, which are phagocytosed by other cells. Importantly, the intracellular constituents are not released into the extracellular milieu where they might have deleterious effects on neighboring cells. On the contrary, cells that die in response to tissue damage or other reasons exhibit very different morphological changes generally called necrosis. The cells that undergo this process swell and burst, releasing their intracellular contents, which can damage surrounding cells and often cause inflammation. Apoptosis refers to a particular morphology in which a chromatin condenses or coalesces to a heterochromatin in one or more masses in the nucleus. It usually settles along still-intact nuclear membrane referred to as margination of the chromatin. One of the essential functions of apoptosis is the elimination of cells in which DNA damages, faulty proliferation or improper adhesion to extracellular matrix that cannot be repaired. In cancer cells, the mechanism of apoptosis induction is broken. Therefore, more and more ideas and hypotheses for selective inducing apoptosis in cancer cells are tested in a growing number of laboratories all over the world. The subject of programmed cell death has been recently discussed in almost 80 000 publications. As it is known, cell apoptosis may be induced by various stress factors (e.g. hypoxia, expression of oncogenes, mutations, DNA damages). On the other hand, apoptosis may be induced via internal or external signals, for instance proteins. Some of such endogenous and exogenous proapoptotic proteins have been found and described. Their genes may be used in modern anticancer therapies.
For example, introducing into cancer cells proapoptotic genes as Bax, Bcl-X5 or E2F-1 significantly increases induction of apoptosis. Some clinical trials concern therapeutic application of a 121-amino acids apoptin originated from chicken anemia virus (CAV). Recent data suggest that apoptosis induced by this protein involves caspases, a family of cysteinyl aspartate-specific proteinases. In vitro results show that apoptin is very active against cancer cells without inducing toxicity to normal cells. This tumor-specific effect may be explained by the nuclear localization of the protein in tumor cells required for its action. Moreover, apoptin is equally active, such as p53-mutant, Bcl-2-overexpressing or BCR-ABL-expressing tumor cells. Other investigations showed that E4orf4 induces apoptosis in cancer cells by linking with 2A (PP2A) phosphatase. Unfortunately, induction of apoptosis by introducing genes encoding proapoptotic proteins has been little known.
One possible mechanism is associated with destruction of mitochondrial membranes and, in consequence, disturbing electrons transport, oxidative phosphorylation and ATP synthesis. Finally, the cell dies but the death is slightly different than that during typical apoptosis induced by caspases due to prolonged time of this process.
Proapoptotic proteins cannot be directly introduced to cancer cells because there are no specific receptors. They are transported through membranes in complexes by special fusion proteins called ligands. Other method is introducing them as genes by vectors and this approach has been already successfully applied. Clinical trials are presently underway to test efficiency of new apoptosis-triggering drugs. A large number of adenoviral agents are being constructed, including replication-incompetent and replication-selective oncolytic adenoviruses. One of them is ONYX-015, a replication-competent virus genetically engineered to selectively replicate in and lyse p53-deficient cancer cells. Other agent, INGN 201, was shown to deliver a p53 expression.
Preclinical studies in human cell lines and animals with head and neck cancers have shown that the p53 gene is transcribed and translated into p53 protein. Respectively, 5% and 58% of patients receiving three intratumoral injections of INGN 201 in conjunction with radiation therapy for over 6 weeks were shown to have achieved complete and partial responses. Other example may be a gene encoding the proapoptotic Vpr protein that was successfully transferred into cancer cells by the HIV-1 virion. These agents are introduced by intravascular infusion or intratumoral or epitumoral injections. An example of a target therapy against cancer is an intravenous administration of liposomal form of tretinoin (ATRA). Treatment of acute promyelocytic leukemia (APL) with ATRA alone or in combination with chemotherapy results in an almost complete remission rate as high as 85% to 95%.
Other proapoptotic anticancer therapeutics is Genasense developed by the Genta Company. Genasense is a phosphothioate oligonucleotide consisting of 18 modified DNA bases. First, the single-stranded DNA molecule must be incorporated into a cancer cell and then target the mRNA by having a complementary sequence to it.
This drug inhibits the production of a protein known as Bcl-2 that is widely expressed in many types of cancer. This up-regulation of Bcl-2 blocks the release of cytochrome C from the mitochondria thereby preventing apoptosis. Furthermore, Bcl-2 appears to be a major contributor to both inherent and acquired resistance to current anticancer treatments. By inhibiting production of Bcl-2, Genasense enables the cancer cells to be killed by apoptosis when treated with current state of the art therapy. Interesting apoptosis-inducing drug is Velcade jointly developed by NCI and Millenium Pharmaceuticals. Activity of Velcade is mainly associated with reversible inhibition of the proteasome and building up many proteins including BAX. In the normal cells, the BAX protein induces apoptosis by blocking the activity of Bcl-2. When BAX level increases, BAX inhibition of Bcl-2 also increases and the cells undergo apoptosis. Non-clinical studies have demonstrated that cancer cells are more sensitive to the effects of the proteasome inhibition than normal cells.
Adachi, S.L.L., Carson, D.A., Nakahata, T., 2004. Apoptosis induced by molecular targeting therapy in hematological malignancies. Acta Haematologica 111, 107-123.
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