The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells

Abstract

Troglitazone (TGZ) is a synthetic thiazolidinedione drug belonging to a group of potent peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists known to inhibit proliferation, alter cell cycle regulation, and induce apoptosis in various cancer cell types. TGZ is an oral anti-type II diabetes drug that can reverse insulin resistance. For more then 100 yr, aspirin, a nonselective cyclooxygenase (COX) inhibitor, has been successfully used as an anti-inflammatory drug. Recently, Aspirin (ASA) and some other nonsteroidal anti-inflammatory drugs (NSAIDs) have drawn much attention for their protective effects against colon cancer and cardiovascular disease; it has been observed that ASA's anti-tumor effect can be attributed to inhibition of cell cycle progression, induction of apoptosis, and inhibition of angiogenesis. In this report we demonstrate for the first time that, when administered in combination, TGZ and ASA can produce a strong synergistic effect in growth inhibition and G(1) arrest in lung cancer CL1-0 and A549 cells. Examination by colony formation assay revealed an even more profound synergy. In Western blot, combined TGZ and ASA also could downregulate Cdk2, E2F-1, cyclin B1, cyclin D3 protein, and the ratio of phospho-Rb/Rb. Importantly, apoptosis was synergistically induced by the combination treatment, as evidenced by caspase-3 activation and PARP cleavage. The involvement of PI3K/Akt inhibition and p27 upregulation, as well as hypophosphorylation of Rac1 at ser71, were demonstrated. Taken together, these results suggest that clinically achievable concentrations of TGZ and ASA used in combination may produce a strong anticancer synergy that warrants further investigation for its clinical applications.

Peroxisome proliferator-activated receptor gamma and early folliculogenesis during an acute hyperandrogenism condition

“…The relationship between PPAR and apoptosis is controversial. It has been reported that the enhancement of PPARg can prevent (42)(43)(44)(45) and mediate apoptosis (46,47). Our data lead us to suggest that the PPARg pathway seems to prevent apoptosis of antral follicles.…”

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

“…An enhancement of the anti-tumor effects of gefitinib by rosiglitazone on A549 cell growth was recently noted suggesting that combination strategies using selective nuclear receptor activators in conjunction with EGFR inhibitors might be effective [92] . More recently, one report showed that the combination of clinically achievable concentrations of troglitazone and nonselective COX inhibitor, aspirin, can produce a strong synergistic effect on the inhibition of lung cancer cell growth and induction of apoptosis [93] . One study demonstrated that combining the PPARγ ligand rosiglitazone with carboplatin dramatically reduced lung tumor growth in vivo [94] .…”

Aspirin enhances doxorubicin-induced apoptosis and reduces tumor growth in human hepatocellular carcinoma cells in vitro and in vivo

“…Especially, use of 300 mg or more of ASA a day for about 5 years reduces the short-term risk of recurrent colorectal adenomas in patients with a history of adenomas or cancer (6). The anticancer activity of ASA is thought to be linked to their ability to inhibit cell proliferation and to induce apoptosis (7). We hypothesized that combination of ASA and DOX might be effective in the treatment of HCC since ASA has been reported to show anticancer effect on HCC (8,9).…”