The combination of a platinum compound and paclitaxel represent the standard initial chemotherapy for ovarian cancer, while doxorubicin has shown some promise in the treat ment of recurrent drug resistant disease. Various studies have investigated drug resistance, but few have compared the drug resistance mechanisms associated with the development of resistance to different drugs. We found that the gene expression changes associated with the development of drug resistance was dependent on the drug used, but the individual lines generated from a given drug were extremely similar to each other. This suggests that while cell lines adopted different mechanisms to develop resistance to different drugs, a given drug and conditions seem to favor similar pathways.

Interestingly, the patterns of expression associated with cisplatin and doxorubicin resistance were more similar to each other than they were to cell lines developed through paclitaxel exposure. This is further supported by the observation that selleck the number of differentially expressed genes shared by cis platin and doxorubicin was greater than the num ber of genes shared by cisplatin and paclitaxel or paclitaxel and doxorubicin. Doxorubicin and paclitaxel resistance can both arise through a multi drug resistance type mechanism, which generally results from overexpression of ATP Binding cassette transporters, while cisplatin resistance is not believe to have a significant MDR component. On the other hand, cisplatin and doxorubicin are both DNA damaging agents, while paclitaxel is a microtubule stabiliz ing agent.

Our data suggest that the overall changes in gene expression tend to reflect the drug target rather than an association with the MDR phenotype. order BAPTA-AM Overall, relatively few genes were simultaneously altered in the 3 drug resistance phenotypes studied, only 18 genes were elevated and 44 genes decreased. Many of these genes were validated and shown to be differen tially expressed at the protein level. Pathway enrichment analysis of these genes revealed that the most significantly enriched pathway was fatty acid metabolism and oxidation. Certain genes consistently downregulated in all the drug resistant lines were particularly interesting. In particular, MSMB was found highly downregulated in drug resistant cells at both the mRNA and the protein levels. Interestingly, MSMB has been found decreased in prostate cancer and has been sug gested to function through its ability to regulate apopto sis. With this function in mind, it is intriguing that we identified MSMB as one of the most downregulated genes following the development of drug resistance for all three drugs. These findings suggest that MSMB or derivatives may be useful in sensitizing ovarian cancer cells to chemotherapy.