Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells.
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.
Xiao
Hang
H
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Zhang
Qiang
Q
Lin
Yong
Y
Reddy
Bandaru S
BS
Yang
Chung S
CS
D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016193:G1 Phase / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D013449:Sulfonamides; D000069059:Atorvastatin; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D019204:GTP-Binding Proteins; D000068579:Celecoxib