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Proteasome Inhibition Circumvents Solid Tumor Resistance to Topoisomerase II-directed Drugs¹

Yasunari Ogiso, Akihiro Tomida, Shuhong Lei, Satoshi ura and Takashi Tsuruo²

Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan [Y. O., A. T., S. L., T. T.]; Kitasato Institute, Minato-ku, Tokyo 108-8642, Japan [S. .]; and Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170-8455, Japan [T. T.]

Physiological cell conditions, such as glucose deprivation and hypoxia, play a role in developing drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase II (topo II), rendering cells resistant to topo II-targeted drugs, such as etoposide and doxorubicin. We show here that inhibition of proteasome attenuated drug resistance by inhibiting topo II depletion induced by glucose starvation and hypoxia. topo II restoration was seen only at the protein levels, indicating that the topo II protein depletion occurred through a proteasome-mediated degradation mechanism. The stress-induced etoposide resistance was effectively prevented in vitro by the proteasome inhibitor lactacystin in both intrinsically resistant and sensitive tumor cells (colon cancer HT-29 and ovarian cancer A2780 cells, respectively). Furthermore, lactacystin effectively enhanced the antitumor activity of etoposide in the refractory HT-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.

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