Cell Protection Mechanisms In Cancer

Exogenous carcinogens and potential mutagens arising from endogenous processes are often prevented from encountering DNA by specific cellular protections mechanisms. These highly diverse mechanisms serve as a further tier of cancer prevention in addition to DNA repair and apoptosis. Often, they protect not only DNA, but cells in general from damage. Some of these mechanisms are very specific and some are very general. In the context of cancer, they are particularly important during two very different phases, viz. (1) during carcinogenesis and (2) during cancer therapy.

A number of low molecular weight compounds are employed in the cell to stabilize macromolecules and membranes, protect against altered osmolarity, buffer the redox state, and quench radicals and specifically reactive oxygen species. These chemically diverse compounds (Table 3.3) comprise polyamines, amino acids like taurine, the tripeptide glutathione, and the lipophilic and hydrophilic vitamins E and C, i.e. tocopherol and ascorbic acid. Glutathione, y-glutamyl-cysteinyl-glycine (GSH), is part of a cellular redox buffer system and its thiol group also reacts readily with radicals. The normal oxidized form of glutathione is its disulfide GSSG, from which GSH can be recovered by glutathione reductase, which uses NADPH as the cosubstrate. GSH is also used in enzymatically catalyzed reactions for similar purposes. So, the selenium-containing enzyme glutathione peroxidase removes hydrogen peroxide generating GSSG. Lack of this enzyme may be one reason why selenium deficiency may increase the risk of cancer. Glutathione also reacts spontaneously with reactive electrophilic compounds, including activated carcinogens. These reactions are strongly accelerated by glutathione transferases (GSTs). The various isoenzymes in this family all catalyze the reaction of glutathione with several substrates, but each enzyme recognizes a different range of compounds. In most cases, carcinogens are inactivated by conjugation with glutathione. The conjugates are further metabolized and eventually excreted.

It is clear from this short description why polymorphisms in GST enzymes catalyzing reactions of glutathione modulate the risk of various cancers (^2.3). In addition, the level of glutathione itself and the ratio of GSSG:GSH are also relevant. However, these same reactions are also relevant in the context of cancer therapy. Cytotoxic cancer drugs also react with DNA and some act by inducing reactive oxygen species. So, both reaction with glutathione catalyzed by GSTs and the quenching of reactive oxygen species by GSH and other radical catchers diminish the efficacy of such drugs in cancer cells, while they protect normal cells. In fact, GSTP1, one isoenzyme of the family, is often overexpressed in cancers becoming resistant to therapy, in some cases as a consequence of gene amplification. Paradoxically, the same enzyme is down-regulated in a few selected cancers such as prostate carcinoma (^19.3).

A similar argument can be made for ionizing radiation. The effects of ionizing radiation on normal cells are mitigated by cellular protection mechanisms, in addition to DNA repair. For instance, polyamines stabilize cellular macromolecules such as DNA and structural RNAs. Tocopherol, ascorbate, carotenoids, and glutathione can all act to quench the effect of hydroxyl radicals and other reactive oxygen species. Therefore, it may in some cases be helpful to deplete such compounds prior to therapy.

GSTs and glutathione peroxidase (abbreviated GPx) are examples of cell-protective enzymes that modulate the effects of many different exogenous and endogenous agents. Others are more tailored towards specific compounds. For instance, metallothioneins are a group of small proteins protecting against toxic metal ions. They contain multiple thiol groups which are highly reactive towards

Table 3.3. Some low molecular weight compounds and enzymes in cell protection

Low molecular weight compound

Function

Protein/enzyme

Function

Glutathione

protection against

Glutathione

removal of H2O2

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