Over-expression of a Mitochondrial DNA Repair Enzyme Protects Normal Cells from Cancer Drugs

Mark R. Kelley, Ph.D.
Indiana University School of Medicine, Indianapolis
NIEHS Grants R01ES005865 and R01ES003456

Background: Current cancer treatments include drugs known as alkylating agents. They work by chemically modifying DNA, which disrupts normal DNA replication and results in cell death. These effects are especially toxic to the rapidly growing and dividing cancer cells to which the drugs are targeted; however, normal cells are inevitably affected as well. Proteins known as DNA repair enzymes are present in cells to target damaged DNA and reverse the modifications caused by alkylating agents. One such enzyme is methylguanine methyltransferase (MGMT). MGMT directly reverses the chemical modification guanine, one of the four building blocks of DNA, allowing normal replication to take place. Scientists have hypothesized that properly targeted DNA repair enzymes could be used to combat drug toxicity in normal cells and alleviate side effects; however, DNA is present both in the nucleus of a cell as well as in mitochondria, and it is currently unknown whether damage to nuclear or mitochondrial DNA plays a larger role in cell toxicity.

Advance: Scientists at the Indiana University School of Medicine studied whether or not MGMT could reverse the toxic effects of alkylating agents. They did this by causing an over-expression of MGMT in cultured human cells and targeted the enzyme either to nuclei or mitochondria. They then exposed the cells to DNA alkylating agents commonly used in chemotherapy. They found that cells overexpressing MGMT had better survival rates than cells expressing low levels of MGMT, and that MGMT targeted to the mitochondria was as effective or better than nuclear-targeted MGMT at preventing cell killing depending on the cell type and chemical agent used.

Implications: These results suggest a potential strategy for reducing the harmful side effects of chemotherapy by making healthy cells more resistant to alkylating drugs. They imply that it may be possible to engineer such cells and introduce them into patients prior to beginning chemotherapeutic regimens. They suggest that DNA repair enzymes such as MGMT are promising focuses of such strategies and that mitochondria, as well as nuclei, are equally important targets of these enzymes.

Citation: Cai S, Xu Y, Cooper RJ, Ferkowicz MJ, Hartwell JR, Pollok KE, Kelley MR. Mitochondrial targeting of human O6-methylguanine DNA methyltransferase protects against cell killing by chemotherapeutic alkylating agents. Cancer Res. 2005 Apr 15;65(8):3319-27.