bay-11-7082 and sabarubicin

The development of chemoresistance is a major obstacle for successful anticancer therapy. Understanding the molecular mechanisms leading to chemoresistance is a rational step to improve the therapeutic efficacy of cytotoxic drugs. Since anthracyclines play an important role in cancer chemotherapy, we have generated a human ovarian tumor cell line resistant to sabarubicin (MEN 10755), the newest anthracycline molecule in clinical development. Expression of the transporter protein MRP that affected sabarubicin uptake, and a reduced DNA topoisomerase II content in A2780/saba cells was observed. Since the poisoning of DNA topoisomerase II results in DNA damage, which is a critical signal for NF-kappaB activation, we explored if this transcription factor has a role in the chemoresistance to anthracyclines. We showed a reduced NF-kappaB activation in the resistant cell line. Moreover, qualitative changes in NF-kappaB dimer formation between the two cell lines were observed. In agreement with the hypothesis of a role of NF-kappaB in mediating drug resistance, we showed that the pharmacological inhibition of NF-kappaB activation attenuated drug resistance in A2780/saba cells whereas it had no effect in A2780 cells. Altogether, these findings show that anthracycline resistance in A2780 cell lines is due to the coexpression of several molecular mechanisms.

Topics: Anthracyclines; Antineoplastic Agents, Phytogenic; Blotting, Western; Cell Line, Tumor; Cell Survival; Disaccharides; DNA Topoisomerases, Type I; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Activation; Etoposide; Female; Gene Expression; Humans; Multidrug Resistance-Associated Proteins; NF-kappa B; Nitriles; Ovarian Neoplasms; RNA, Messenger; Signal Transduction; Sulfones; Time Factors; Vinblastine