Effects of mitomycin C and other DNA crosslinking agents on gene expression: Modulation of cancer cell multidrug resistance in cell culture and in vivo.

摘要

Our laboratory is concerned whether the distribution of chemically-induced DNA damage is non-random at the level of individual genes. Using changes in gene expression as a marker for DNA damage, we have previously demonstrated that genotoxic chemical carcinogens preferentially alter the expression of inducible genes without affecting constitutive genes. In this work it was demonstrated the MMC, a prototypical chemical carcinogen, did not act through the non-specific "UV response" pathway to exert these effects on inducible genes. It was also found that it is unlikely that these effects are due to the indirect MMC action on the binding of several ubiquitous transcription factors. Lastly in this regard, it was observed that MMC adducted to cis-acting elements could cause both significant increases in decreases in factor binding, in a factor- and adduct level-specific manner. This is in keeping with our hypothesis that MMC and other chemical carcinogens preferentially alter the binding and activity of specific transcription factors to their cis-acting elements, leading to changes in expression. We also examined whether these preferential effects could be applied to improve cancer chemotherapy, specifically to reduce aspects of the multidrug resistance (MDR) phenotype due to an ATP-dependent efflux pump, P-glycoprotein (Pgp). We found that MMC pre-treatment significantly suppressed mdr1b mRNA as well as expression of its protein product, Pgp and function, leading to an increase in cell killing by a Pgp substrate chemotherapeutic agent, doxorubicin. This effect occurred in tumor cells derived from the liver, colon, breast, glial cells and leukocytes and with the DNA crosslinking agents MMC, cisplatin, carboplatin and chromium (VI). It was also demonstrated that this not only affected Pgp expression, but also that of other MDR phenotype proteins including MRP, LRP, and two GST isoforms. This phenomenon occurred in cells in culture, cells implanted into immune-deficient mice, and most importantly, in human patients. Thus it is a general phenomenon. Taken together, these studies should lend a better understanding of the role of DNA damaging agents both within the realm of cancer formation and with applications for improved cancer treatment.