Defects in the apoptotic machinery of cancer cells: role in drug resistance
Introduction
Various forms of chemotherapy and ionizing radiation represent the main weapons used to kill tumor cells. Although successful treatment of many hematological and childhood malignancies has been achieved, the most common tumors (especially solid tumors) are still resistant to these types of treatment. Therefore, it is clear that the development of new therapies based on modern knowledge of tumorigenesis, mechanisms of tumor cell death, and resistance to treatment is one of the important areas in biomedical research.
The therapeutic goal in cancer is to trigger tumor-selective cell death (for review see [1], [2]). In principle, there are at least two strategies to achieve this goal. Firstly, it is important to deliver the drug to the tumor-containing tissue in a manner that favors its accumulation in cancer cells. Secondly, it is important to selectively activate the cell death machinery of tumor cells and thus spare normal cells and tissues. Here, we would like to discuss differences in efficiency of the apoptotic machinery in cancer cells and how to use this knowledge to increase the sensitivity of tumor cells to treatment.
Section snippets
The composition of the apoptotic machinery
There are thousands of biological, chemical and physical agents that can cause cell death. Most of these agents induce either apoptosis or necrosis in a dose-dependent manner. Intriguingly, despite the multitude of intracellular targets for the different triggers, many of these agents induce apoptosis through the activation of just a few common pathways (Fig. 1).
Does dysregulation of apoptosis play any role in resistance of tumor cells to treatment?
Anticancer drugs are designed to kill tumor cells via activation of the cellular death machinery. However, in spite of this tumor cells often remain alive and continue to grow. How do tumor cells evade drug-induced apoptosis? Which anti-apoptotic mechanisms are activated in malignant cells? Is it possible to bypass these mechanisms to improve the sensitivity of tumor cells to treatment? All these questions remain to be answered.
Concluding remarks
The ability of malignant cells to evade apoptosis is a hallmark of cancer, and their resistance to apoptosis constitutes an important clinical problem [1]. Cell death pathways in tumor cells appear to be much more complicated than was originally anticipated. Resistance of many tumors to chemotherapy is associated with either defects or dysregulation of different steps within the cell death machinery (Table 1). None of the components of this machinery operates in isolation, and the activation of
Acknowledgements
Work in the authors’ laboratory is supported by grants from the Swedish Medical Research Council (03X-2471), and the Swedish (3829-B01-06XAC) and Stockholm (02:145) Cancer Societies. Many thanks to Dr. J.D. Robertson for stimulating discussions and for carefully reading the manuscript. We apologize to those authors whose primary references were not cited due to space limitations.
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