Seleno-L-Methionine Modulation of Nucleotide Excision DNA Repair Relevant to Cancer Prevention and Chemotherapy

Abstract

Organic selenium compounds are known to prevent certain cancers although mechanisms may be complex. A widely-held view is that selenium compounds can induce apoptosis in cancer cells, or more precisely, in aberrant cells that are undergoing clonal evolution somewhere along the carcinogenesis process. There are at least 20 different selenium compounds, inorganic as well as organic, that have been used in various published studies. Extrapolation between studies should therefore be undertaken with caution. Similarly, it will be important to ascertain the physiological relevance of the selenium concentrations used in some studies. While cancer prevention by selenium is well-established, recently, organic selenium in the form of pure seleno-L-methionine (SeMet) has been used in combination with cancer chemotherapy drugs. SeMet can induce a DNA repair response in some cell types including bone marrow. Cancer cells generally lack a SeMet-inducible DNA repair response. Thus, SeMet appears to selectively regulate a DNA repair pathway and thereby potentially alter responses to cancer chemotherapy drugs. The specific pathway implicated, nucleotide excision DNA repair (NER) is required for repair of cisplatin or carboplatin DNA damage relevant to chemotherapy. Moreover, some studies have implicated NER as a factor in carcinogenesis processes. Thus, the capacity of SeMet to selectively regulate NER may prove useful in both therapeutic and preventive contexts.

Figure 1. SeMet treatment, 15 μM, 15 hrs, leads to XPC protein stabilization or induction in mouse bone marrow (left) but not in H1299 human lung cancer cells (right)

In fact, SeMet may destabilize XPC in some cancer cell types. The idea is that SeMet pre-treatment “sets the stage” for DNA-damaging treatments by altering XPC concentrations and hence the relative NER rates in normal cells and in cancer cells. Bone marrow was protected from carboplatin while cancer cells were sensitive to carboplatin. Adapted from JL Fischer et al, references and .

Figure 2. Diagram of selective DNA repair response evoked by SeMet

One factor is p53 status, which is functional in normal cells, but mutant or nonfunctional in the majority of cancer cells. XPC is regulated by p53.