Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs

Physiological cell conditions, such as glucose deprivation and hypoxia, pla y a role in developing drug resistance in solid tumors. These tumor-specifi c conditions cause decreased expression of DNA topoisomerase II alpha (topo II alpha), rendering cells resistant to topo II-targeted drugs, such as et oposide and doxorubicin, We show here that inhibition of proteasome attenua ted drug resistance by inhibiting topo II alpha depletion induced by glucos e starvation and hypoxia, topo II alpha restoration was seen only at the pr otein levels, indicating that the topo II alpha protein depletion occurred through a proteasome-mediated degradation mechanism. The stress-induced eto poside resistance was effectively prevented in vitro by the proteasome inhi bitor lactacystin in both intrinsically resistant and sensitive tumor tells (colon cancer HT-29 and ovarian cancer A2780 cells, respectively). Further more, lactacystin effectively enhanced the antitumor activity of etoposide in the refractory MT-29 xenograft, These results indicate that lactacystin could serve as a new therapeutic agent to circumvent resistance to topo II- targeted chemotherapy in solid tumors.