Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs.
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 IIalpha (topo IIalpha), 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 IIalpha depletion induced by glucose starvation and hypoxia. topo IIalpha restoration was seen only at the protein levels, indicating that the topo IIalpha 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.
Ogiso
Y
Y
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Tomida
A
A
Lei
S
S
Omura
S
S
Tsuruo
T
T
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015152:Blotting, Northern; D002453:Cell Cycle / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D015151:Immunoblotting; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D009097:Multienzyme Complexes; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; C067713:lactacystin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004250:DNA Topoisomerases, Type II; D005947:Glucose; D000111:Acetylcysteine; D008727:Methotrexate