Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity.
OBJECTIVE
The nonsteroidal antiinflammatory drug sulindac is a promising chemopreventive agent against colon cancer. Here, we address whether sulindac enhances the anticancer effects of the proteasome inhibitor bortezomib (PS-341) in colon cancer cells.


METHODS
The synergistic effects of sulindac with bortezomib were evaluated by cell death, colony formation assay, DNA fragmentation, and tumor progression of DLD-1 xenografts. Reactive oxygen species (ROS) generation was detected using carboxy-H2DCFDA or dihydroethidium. Oxidative stress was evaluated by heme oxygenase-1 induction and stress-activated mitogen-activated protein kinases p38 and c-Jun-NH2-kinase phosphorylation. Oxidative DNA damage was evaluated by histone H2AX phosphorylation and accumulation of 8-hydroxy-2'-deoxyguanosine.


RESULTS
Sulindac and its metabolites enhanced the anticancer effects of bortezomib in DLD-1 and BM314 colon cancer cells. Sulindac induced ROS generation and enhanced bortezomib-mediated oxidative stress and subsequent DNA damage. Their combined effects were highly sensitive to free radical scavengers L-N-acetylcysteine and alpha-tocopherol, but were much less sensitive to a p38 inhibitor SB203580.


CONCLUSIONS
Sulindac synergistically augments the anticancer effects of bortezomib primarily through cooperative ROS generation and oxidative DNA damage, thereby representing a novel combination therapy against colon cancer.
Minami
Takae
T
First Department of Internal Medicine, Graduate School of Medicine, Sapporo Medical University, Sapporo, Japan.
Adachi
Masaaki
M
Kawamura
Rina
R
Zhang
Yubin
Y
Shinomura
Yasuhisa
Y
Imai
Kohzoh
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death; D003110:Colonic Neoplasms / Q000473:pathology*; D004249:DNA Damage; D018450:Disease Progression; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D013467:Sulindac / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013467:Sulindac; D000069286:Bortezomib