Story of Discovery
Email this pageHarnessing Apoptosis to Destroy Cancer Cells
On this page:In 1972, John Kerr, Andrew Wyllie, and Alistair Currie published a foresighted paper describing a little known and curious form of cell death that today is one of the most intensively studied topics in modern biology. The researchers reported on a type of cell death - a programmed cell suicide - that was distinctly different from the long-recognized process of cell death known as necrosis. Necrosis occurs when a cell becomes acutely injured and ruptures, causing inflammatory cells to rush in to clear away the debris. Programmed cell suicide, in contrast, is clean and quick and involves a predictable sequence of structural changes that cause a cell to shrink and be rapidly digested by neighboring cells.
Although biologists have long known that cell suicide plays an important role in sculpting tissue within developing embryos, Kerr, Wyllie, and Currie were the first to observe that programmed suicide - which they labeled apoptosis - also occurs in mature cells. They also were the first to hypothesize that apoptosis plays a broad role in normal life processes, and its failure contributes to a variety of diseases, including cancer.
Several years later, Nobel Prize winners John Sulston, H. Robert Horvitz, and colleagues used the microscopic roundworm C. elegans to explore how a single fertilized egg develops into an adult organism with multiple cell types. As they painstakingly followed each of the developing worm's 1,090 cells to their ultimate fate, they were surprised to see that 131 cells died via apoptosis as the worm matured into adulthood. With this observation, they substantiated the prediction made by Kerr and his colleagues that apoptosis occurred beyond embryogenesis. By 1986 Horvitz and colleagues determined that two genes - ced-3 and ced-4 - produce proteins that are required for apoptosis to proceed in C. elegans. Horvitz's work demonstrated conclusively that programmed cell suicide is genetically controlled. Horvitz's team later identified a third apoptosis gene, ced-9, which produces a protein to inhibit apoptosis. Subsequent analysis demonstrated that these genes have been broadly conserved throughout evolution, indicating the ubiquitous importance of apoptosis among animals. These findings served to heighten researcher interest in this process.
Over the last 15 years, using emerging technologies, scientists have confirmed that apoptosis plays a central role within developing organisms by shaping the neural and immune systems and molding tissue specificity. They also demonstrated that apoptosis helps to establish a natural balance between cell death and cell renewal in mature animals by destroying excess, damaged, or abnormal cells.
Additional studies have revealed that apoptosis occurs through two distinct cellular pathways. The "extrinsic" pathway is activated by the binding of death activator proteins to the cell surface. The "intrinsic" pathway is launched by signals inside the cell, such as damage caused by radiation or toxins, the withdrawal of critical survival factors (growth factors, hormones), or disturbances in the cell cycle. Both pathways converge inside the cell, turning on a central executioner family of proteins resembling ced-3 that are now known as caspases. Caspases act as knives, cutting up proteins inside the cell and digesting the cell from within. Because caspases become activated early in apoptosis and irreversibly launch a cell's death machinery, scientists realized that finding their trigger would offer the unprecedented opportunity to control cell death and survival.
More recently, scientists have been exploring the role of mitochondria (the energy-producing structures of cells) in apoptosis. In 1996, Xiaodong Wang and colleagues discovered that cytochrome c, a critical protein component of the mitochondria, is a caspase activator. With this finding, scientists began to study the mitochondria to determine how apoptosis functions in the cell, and malfunctions in disease.
Connecting Failed Apoptosis and Cancer
The link between apoptosis and cancer was not established until David Vaux and colleagues demonstrated in 1988 that the bcl-2 gene specifically blocks death of B cells in follicular lymphoma (an immune system cancer). In 1990, Stanley Korsmeyer, David Hockenbery, and colleagues characterized the normal bcl-2 as a suicide "brake" gene - it produces a protein that blocks apoptosis. These and several related milestone findings 1 greatly energized apoptosis research by establishing that increased cell division was not the only way that tumors could develop. Cells could also become potent promoters of tumor growth by avoiding programmed cell death. In some lymphoma patients, the abnormal form of the bcl-2 gene is overactive, causing the anti-apoptosis protein to be overproduced. Cancer develops as more and more B cells are generated and fail to die.
Throughout the 1990s, scientists gathered considerable information about bcl-2. They determined that increased bcl-2 protein production occurs in several cancers, including B cell leukemias, lymphomas, colon and prostate cancers, and neuroblastoma, and is linked to poor disease outcome. In addition, overexpression of the bcl-2 gene may confer resistance to chemotherapeutic drugs. In 1997 scientists determined that bcl-2, which is found on the outside of mitochondria, prevents apoptosis by acting before cytochrome c is released from inside mitochrondria. Scientists now are working to develop a complete picture of how bcl-2 acts so that they can improve the suicide-provoking effects of cancer treatments as well as thwart a cancer cell's ability to evade these drugs.
Since the discovery of bcl-2 and its role in apoptosis, scientists have determined that this dauntingly complicated process has many genetic controls. For example, the p53 protein, known as the guardian of the human genome, serves as an important tumor suppressor because it either blocks the cell division of a genetically damaged cell or triggers apoptosis by causing damage to the mitochondria and cytochrome c release. In 55 to 70 percent of human cancers, however, genetic mutations render the p53 protein deficient and cells with DNA damage can continue to accumulate. Loss of p53 function is associated with tumor aggressiveness and resistance to anti-cancer treatments.
Mounting evidence indicates that the acquired ability to resist apoptosis is a hallmark of most, and perhaps all types of cancer. As scientists learn more about how apoptosis is thwarted by cancer, they are also gaining a greater understanding of why many tumors are resistant to the cell suicide inducing effects of radiation and chemotherapy. These insights can inform efforts to overcome treatment resistance and offer important clues about new drugs that target genes and protein products in the apoptosis pathways to encourage selective cell death. Researchers are exploring how apoptosis is regulated, how it might be repaired through genetic therapies, and how it can be selectively triggered, through tailored treatments, to induce suicide in cancer cells while leaving healthy cells alone.
Triggering Apoptosis with New Cancer Drugs
Clinical trials are currently underway to test the efficacy of new apoptosis-inducing drugs. Velcade™, a new agent jointly developed by NCI and Millenium Pharmaceuticals, targets the proteosome, a device inside a cell that functions like a cellular "garbage disposal," removing abnormal, aged, or damaged proteins. By blocking the activity of the proteosome, Velcade causes proteins, to build-up in the cell. One of these proteins is BAX. In the normal cell, the BAX protein promotes apoptosis by blocking the activity of the anti-apoptosis protein, bcl-2. As BAX levels increase in response to Velcade, BAX inhibition of bcl-2 also increases and the cell ultimately undergoes apoptosis.
Velcade may prove to be a versatile cancer treatment because it appears to be equally effective against cancers that do or do not overexpress the bcl-2 gene and seems to overcome a tumors ability to develop chemoresistance. In a Phase II clinical trial of patients with progressing multiple myeloma, Velcade stabilized the disease in 77 percent of the trial participants. Based on this encouraging result, researchers are planning a Phase III trial to compare Velcade to dexamethasone, a therapy now used to treat multiple myeloma. Other Phase II trials will determine the drug's effectiveness in treating breast cancer, non-small cell lung cancer, melanoma, sarcoma, chronic myelogenous leukemia, non-Hodgkin's lymphoma, and neuroendocrine and renal cancers.
Genasense™ is another apoptosis-inducing agent that is being tested for its clinical use. Developed by the Genta Company, this drug blocks the production of the bcl-2 protein and leaves cancer cells more vulnerable to apoptosis-inducing chemotherapies. NCI and Genta are cosponsoring clinical trials in lung cancer and leukemia patients to determine whether pretreatment with this drug followed by state-of-the-art chemotherapies improves treatment outcome.
1 For example, see Lockshin and Zakeri. Programmed cell death and apoptosis: origins of the theory. Nature Reviews Molecular Cell Biology. 2: 542-550. 2001