Although the various single base lesions re quire different lesion specific glycosylases, APE1 is com mon to BER and incises the backbone of the DNA strand selleck compound and facilitates gap filling by DNA PolB. Therefore, the ac tivity of APE1, essential for BER, determines the repair capacity of mono methylation induced by alkylation agents including MMS and melphalan. In addition, DNA re pair activity is associated with the sensitivity Inhibitors,Modulators,Libraries of different agents targeting DNA which mainly cause different types of lesions including cisplatin, 5 FU, bleomycin, and ionizing radiation. Although the detailed mechanisms of the repair activity of APE1 in drug resist ance remain unclear, these observations imply a more im portant role of APE1 in promoting cell survival though a DNA repair dependent mechanism.

We recently observed that APE1 was highly expressed in bone marrow stromal cells in MM patients compared to the normal donors. This study provided a plausible explanation to the drug resistance of MM by APE1 in that APE1 regulates cytokines, including IL 6 and IL 8, produced in BMSCs through redox regulation of NFB and AP 1. This study merely focused on the role of the microenvironment Inhibitors,Modulators,Libraries of MM. However, our present results indicate that the redox activity of APE1 is not involved in acquired melphalan resistance as we expected. We actually observed the reduction of IL 6 8 mRNA in redox activity deficient cells, and the reduction of IL 6 8 expression has a minor Inhibitors,Modulators,Libraries im pact on cell survival after melphalan treatment.

The paracrine agents from the BMSCs in the microenviron ment of the bone marrow are the major source of cytokines and growth factors for MM cell survival, hence, it is probable that the autocrine cytokines from Inhibitors,Modulators,Libraries MM cells have little effect on drug resistance. Interestingly, we found that APE1 regulates the sensitiv ity of MM cells to melphalan by affecting MDR1 expres sion. This MDR1 regulatory role of APE1 is exclusively dependent on the integrity of acetylation sites at K6 K7 as reported previously. A previous study indicated that the MDR1 expression level was associated with low intra cellular accumulation and low cytotoxicity of melphalan in different hematopoietic cancer cell lines, including seven MM cell lines. In accord with our study, the MDR1 inhibitor successfully reversed melphalan resistance in MDR1 overexpressed HL 60 cells.

However, the regulatory role of APE1 in melphalan sensitivity occurs only partially through MDR1 expression. As shown Inhibitors,Modulators,Libraries in Figure 6, knock down of MDR1 in APE1 overexpressed RPMI 8226 cells only partially restores sensitivity to melphalan compared to the MDR1 knockdown in RPMI 8226 cells. In this present study we are the first to identify, to our knowledge, that the APE1 DNA repair function, together with acetylation modification, plays the most important role in melphalan selleck MEK162 resistance.