APOPTOSIS, CANCER DEVELOPMENT AND A NEW OPTION FOR BETTER TREATMENT

 

Assoc. Prof. Dr. Engin ULUKAYA

Medical Faculty of Uludag University, Department of Biochemistry, 16059, Bursa, TURKEY

 

Cell death classically results from injury by agents such as toxins and ischemia, affects cells in groups rather than singly, and evokes exudative inflammation when it develops in vivo. This type of cell death is called necrosis. However, another type of cell death was later defined, and was called programmed cell death (apoptosis). The study of apoptosis did not attract much attention for quite a long time. However, research on apoptosis has recently made a priceless impact on a number of both physiological (e.g. remodelling of tissues, embryogenesis) and pathological conditions (e.g. degenerative diseases, autoimmun disorders, and, to a great extent, cancer) since it was first introduced in 1972. Apoptosis is different to necrosis in some ways. For example, inflammatory response which can cause further damage to surrounding tissue does not take place in apoptosis, while it is evident in necrosis because of the leakage of cell content into the intercellular space through cell membrane that is disrupted by necrosis-causing agents. While necrosis might naturally occur in the centre of tumor mass due to insufficiency of blood supply, apoptosis is rather implicated in the process of carcinogenesis.

Tumor growth is determined not only by increased cell division, but also by decreased rate of physiologically-occurring cell death (apoptosis) in the multicellular organisms. Most, if not all, cancer cells acquire resistance to the various mechanisms that lead to apoptosis. Thereby, tumor cells escape apoptosis. This resistance is accomplished either by continual action of deregulated proto-oncogens (e.g. bcl-2) which ensure cells to maintain abnormally prolonged life span or by inactivation of tumor suppressor proteins (e.g. p53) which promote cell death when required.

Apoptosis of DNA-damaged cells may constitute a physiological antineoplastic mechanism to protect the organism from cancer development by eliminating cells that might otherwise replicate the damaged DNA and lead to mutations and eventually to cancer. Hence, it becomes more evident that the balance between cell proliferation and cell death determines the normal tissue homeostasis. Moreover, there are more mechanisms for tumor cells to grow by escaping apoptosis, all of which ensures tumor growth. There are a number of ways in order for tumor cells to escape apoptosis.  Among these ways,  Fas and FasL interactions, presence of decoy receptors, decreased Bax expression,  overexpression of FLIP (in mouse model), overexpression of caspase inhibitors (cIAP2, Survivin), continual activation of telomerase are particularly implicated. As well as blocking pro-apoptotic pathways, cancer cells can upregulate anti-apoptotic pathways. The growth-factor-mediated activation of phosphatidylinositol 3-kinase (PI3K) is  particularly important in this regard. Apoptosis is also implicated in the mechanism of cytotoxicity of a variety of chemotherapeutic agents (anti-cancer drugs). Therefore, it is thought that understanding how the cell death program is initiated by these drugs or any other kind of insults, and hence why it fails to work for certain drugs, offers a novel approach to overcoming the clinical problem of drug resistance (Makin and Hickman, 2000).

Presuming people are different to each other in terms of their apoptosis-related protein expressions, it can easily be concluded that individual variations in apoptotic program may cause differencies in the anti-cancer drug response.  Taken together, the understanding of discrete apoptotic pathways will obviously contribute not only to the explanations of the development of cancer, but also the development of new strategies toward the prevention and therapy of cancer.

In the treatment of cancer, one of the major modes of action of chemotherapeutic drugs is known to be via the activation of apoptosis. It is thought that understanding how the cell death program is initiated by following these drugs or any other kind of insults, and hence why it fails to work for certain drugs, offers a novel approach to overcoming the clinical problem of drug resistance  (Makin and Hickman, 2000). The drug resistance, in other words chemo-resistance, is one of the nightmare scenarios, which may be encountered during treatment of cancer. To overcome this problem, the chemo-resistance (or even chemo-sensitivity) to particular chemotherapeutics can be tested in vitro on individual tumor tissue samples or biopsi specimens removed from cancer patients.  This approach looks as if it is really going to revolutionise the way we use cancer drugs (Untch et al., 2003; Whitehouse PA et al., 2003; Kurbacher CM et al., 2003).    

 

Makin G, Hickman JA.  Cell Tissue Res 301:143-52, 2000

Untch M, et al. Recent Results Cancer Res: 161:146-158, 2003

Whitehouse PA et al. Anticancer drugs: 14: 369-375, 2003

Kurbacher CM et al. Recent Results Cancer Res 161:221-230, 2003