Previous studies in animal models have shown enhanced efficacy of a combined treatment of
statins and Nonsteroidal anti-inflammatory drugs against
colorectal cancer development. In our study, we investigated the combinational effects of
atorvastatin and
celecoxib in 2 human
colon cancer cell lines HCT116 and HT29.
Celecoxib moderately inhibited the growth of both cell lines with a similar IC(50) of 40-50 microM, whereas
atorvastatin showed stronger growth inhibitory effect in HCT116 cells than in HT29 cells (IC(50) of 5-8 microM vs. 30-35 microM)
after treatment for 48-72 hr. The combination of these 2 agents produced strong synergistic actions, as determined by isobologram analysis. Flow cytometry analysis indicated that the combination treatment for 24 hr caused extensive cell cycle arrest in G0/G1 phase; whereas at 48 hr or longer, apoptosis was induced significantly. The effects produced by the combination were much stronger than that by
atorvastatin or
celecoxib alone. Our results further demonstrated that the combinational effects of
atorvastatin/
celecoxib were associated with increased levels of p21(Cip1/Waf1), p27(Kip1), and phospho-JNK; decreased levels of phospho-AKT and hyper-phosphorylated Rb; and activation of
caspase cascade.
Atorvastatin/
celecoxib combination also selectively modified membrane localization of
small G-proteins, such as RhoA, RhoB and RhoC, which may contribute to the anti-
cancer effects. Taken together, the results demonstrated a strong synergy between the actions of
atorvastatin and
celecoxib in growth inhibition and killing of human
colon cancer cells. The present work suggests the possible therapeutic application of this combination and provides leads for mechanistic and
biomarker investigations in clinical trials.